RU2745584C1 - Method for accelerating reparative osteogenesis in bisphosphonate osteonecrosis - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: invention refers to medicine, particularly dentistry and maxillofacial surgery, and discloses a method for accelerating reparative osteogenesis in bisphosphonate osteonecrosis, involving use of Chonsurid dissolved in riboflavin and hyaluronic acid, with subsequent addition of the obtained mixture to the solar composite in a given ratio.EFFECT: invention enables accelerating bone grafting after removal of necrotized bone in bisphosphonate osteonecrosis, eliminating infection by reliable sealing of the wound and can be used in operations for recovering lost bone tissue.1 cl, 4 dwg, 2 ex

Description

The invention relates to medicine, in particular, dentistry and maxillofacial surgery, and can be used in operations to restore the lost volume of bone tissue in bisphosphonate osteonecrosis of the jaw bones.

It is known that in a number of pathological conditions of the body associated with impaired reparative osteogenesis, such as fractures of the jaw bones complicated by osteoporosis, infection and weakened immunity, false joints and postoperative defects of the upper and lower jaws after cystectomies and cystotomies, targeted stimulation of bone formation is required. which is performed by a surgeon by performing an osteoplasty operation.

To accelerate the reparative process, osteoplastic biomaterials are actively used, which are inherent in osteoinductive and / or osteoconductive properties, and the first option is most preferable, since osteoinduction in dentistry and maxillofacial surgery actually means osteogenesis itself, dentinogenesis and the growth of the periodontal ligament.

The true osteoinductive bone biomaterial is only the patient's own bone, however, its scarcity and difficulties in collection and storage have led to the wider use of analogs - allogeneic bone, where the donor is another individual. Therefore, today, modifications of osteoplastic materials based on calcium hydroxide are very widely used, for example, in the form of porous hydroxyapatite ceramics and tricalcium phosphate (Tanaka, T., Komaki, N., Chazono, M., Kitasato, S., Kakuta, A., Akiyama, S., Marumo, K. Basic research and clinical application of beta-tricalcium phosphate (β-TCP). Morphologie. 2017; 101 (334): 164-172. Https://doi.org/10.1016/j.morpho. 2017.03.002), as well as bone substitute biomaterials based on bone collagen and morphogenetic proteins (Song, Y., Wan, L., Zhang, S., Du, Y. Biological response to recombinant human bone morphogenetic protein-2 on bone-implant osseointegration in ovariectomized experimental design.Journal of Craniofacial Surgery. 2019; 30 (1): 141-144.https: //doi.org/10.1097/SCS. 0000000000004992). All of the biomaterials listed above have only osteoconductive properties; this concept includes the ability of the material to serve as a matrix, the basis for the growth of newly formed bone tissue. For the manifestation of osteoinductive properties, growth factors and other substances stimulating osteogenesis, for example, sulfated or non-sulfated glycosaminoglycans (hyaluronic acid), must be present in the composition of such biomaterials.

In this regard, the problem of accelerating reparative osteogenesis is of great relevance and the development of a method for accelerating reparative osteogenesis using osteoplastic materials is of great practical importance.

One of the dangerous complications of antiresorptive therapy in the treatment of metastatic lesions of skeletal bones (in breast and prostate cancer), multiple myeloma in cancer patients, as well as osteoporosis, using pyrophosphate analogs, is bisphosphonate osteonecrosis of the jaws. This complication is clinically manifested in the form of exposure and subsequent necrosis of the entire area of the upper or lower jaw, and necrosis can affect not only the cortical bone, but also the bone marrow itself. It is reliably known that bisphosphonates, the action of which is mainly in blocking bone self-renewal due to transformations in the cellular structure of osteoclasts, have a sufficiently high affinity for bone tissue, accumulate in it until they are resorbed by a new generation of osteoclast cells, which is a long-term and intractable phenomenon. In this regard, even with the abolition of the use of bisphosphonates in patients with bisphosphonate osteonecrosis of the jaw bones, long-term non-healing foci of bone tissue destruction remain, in which the process of self-renewal of bone tissue is stopped.

Such necrotic areas of bone are surgically removed to a healthy bone, the operation is similar in nature to sequestrectomy and compactosteotomy for osteomyelitis of bone tissue. Then, in order to increase the efficiency of reparative osteogenesis, the postoperative bone cavities are filled with autologous bone, porous hydroxyapatite ceramics, bone collagen, as well as other biomaterials used to stimulate reparative processes in the jaw bones: Bialgin, Osteogenox, Biomatrix, Collapan and others. All of them, to one degree or another, have osteotropic, hemostatic and antibacterial properties and immune inertness, have positive and negative aspects.

In the aspect of acceleration of reparative osteogenesis in bone cavities after removal of the affected areas of the jaw bone tissue in bisphosphonate osteonecrosis, the closest to the proposed method in technical essence and the achieved result is the use of a polysaccharide of animal origin honsuride to fill postoperative bone cavities (RU 2112550 C1, application for invention RU No. 94027755 / 14 from 20.07.1994, MGZh A61K 6/097).

It was found that the use of honsuride accelerates the course of reparative osteogenesis in the postoperative bone cavities of the jaws with a sufficient hemostatic and anti-inflammatory effect, as well as good biocompatibility and a simple method of application.

At the same time, when using honsuride, the rate of reparative osteogenesis is low, since the formation of a full-fledged bone regenerate in the postoperative bone cavity occurs no earlier than 6 months after surgery. In addition, with bisphosphonate osteonecrosis of the jaw, most often bone damage occurs along with the oral mucosa, this requires isolation and sealing of the wound from saliva due to the high likelihood of secondary infection, which is not always possible to provide only through plastic surgery with local tissues.

The task was set: to accelerate the formation of bone regenerate after removal of necrotic bone in bisphosphonate osteonecrosis, excluding infection due to reliable sealing of the wound.

The problem was solved by using a mixture of honsuride, riboflavin and hyaluronic acid, introduced into the composition of a solar composite, cured after being placed in a wound under the influence of ultraviolet rays with a power of 450 mW with a wavelength of 450-470 nm for 40 seconds.

Honsuride is used in the form of a sterile demineralized and lyophilized (devoid of antigenic activity) powder, which is a polysaccharide of animal origin, which promotes the formation of new collagen microfibrils necessary to restore the trabecular structure of bone tissue during reparative osteogenesis in the bone cavities of the jaws in the postoperative period.

Riboflavin (vitamin B2) accelerates the growth and regeneration of cells, participates in the detoxification of toxins and other harmful substances, has an antioxidant effect, and regulates redox processes. It is known that riboflavin degrades in the light (therefore it is recommended to store it in a dark place), however, when exposed to high-intensity ultraviolet rays, riboflavin is activated, as a result of which it is able to cross-link collagen fibers (Sources: https://www.vesti.ru /doc.html?id=3248406; https://news.cornell.edu/stories/2020/03/two-step-method-patches-herniated-disc).

Hyaluronic acid is an active chondroprotective agent, has a stimulating effect on reparative processes in structures of connective tissue origin, and also helps to inhibit dystrophic post-traumatic processes in them. The mechanism of the reparative action of hyaluronic acid is the stimulation of the synthesis of glycosaminoglycans and collagen.

The essence of the therapeutic effect of the developed method is as follows. Exposure to ultraviolet rays with a power of 450 mW with a wavelength of 450-470 nm for 40 seconds activates riboflavin, as a result of which honsuride from the mixture and collagen fibers from the wound combine, forming a strong and airtight bone filling together with the heliocomposite. Within a short period of time (1-6 hours), under the stimulating effect of 2% hyaluronic acid, pluripotent cells begin to migrate into the wound from intact areas of bone tissue, contributing to the acceleration of reparative osteogenesis and the formation of a trabecular structure of the newly formed bone, which completely replaces the heliocomposite in 2-3 months ...

The method is carried out as follows. Dilution of 40 mg of honsuride in riboflavin and 2% hyaluronic acid is carried out, followed by the addition of the resulting mixture to the heliocomposite at the rate of 40 mg of honsuride per 20 mg of riboflavin, 40 mg of 2% hyaluronic acid and 120 mg of the heliocomposite. The resulting mixture is applied on a spatula into the wound, gently tamping along the edges of the bone wound and cured using a dental photopolymerization lamp with ultraviolet rays of 450 mW with a wavelength of 450-470 nm for 40 seconds. The result is a strong hermetic bone patch in place of the bone wound, which does not require additional isolation from saliva with a flap from local tissues.

The experience of using the developed method showed that in all cases of its application, there is an acceleration of reparative osteogenesis without inflammatory complications and relapses of the disease, confirmed by clinical examples, which are given below.

1. Patient S., 55 years old, complained of pain in the region of the upper jaw on the left, bad breath, periodic appearance of pus in the oral cavity in the area of exposed bone areas around the 22, 23, 24 teeth (Fig. 1). From the anamnesis, it was established that the patient was observed by an oncologist with a diagnosis of Primary multiple cancer of the left breast, T2N1M0, condition after complex treatment (left mastectomy, radiation, bisphosphonate therapy): progression in the pelvic bone, femoral head, in the jawbones, stabilization of the process ". The patient took 40 mg of zoledronic acid intravenously once every 2.5 months for 3 years.

Treatment. Under infiltration and conduction anesthesia Sol.Ultracaini 4% with adrenaline 1: 100000, an operation was performed with the removal of the palatine cortical plate around 22, 23, 24 teeth for bisphosphonate osteonecrosis of the upper jaw (Fig. 2) with curettage of the wound and removal of granulations. During the operation, the postoperative bone cavity with a diameter of 35 mm is filled with a mixture of honsuride, riboflavin and hyaluronic acid, introduced into the composition of a heliocomposite, cured after being placed in a wound under the influence of ultraviolet rays with a power of 450 mW with a wavelength of 450-470 nm for 40 seconds.

As a result, a reliable wound sealing was achieved and an acceleration of reparative osteogenesis was ensured, which was confirmed by the results of further clinical observation. Dynamic observation in the early postoperative period (1-7 days) showed that the patient had no pain syndrome, suppuration and edema of the peri-maxillary soft tissues. X-ray examination in the late postoperative period (after 3 months) showed that the healing of the postoperative bone defect was completed with the formation of a full-fledged bone regenerate with an average density of 450 Hounsfield units.

FIG. 1 shows a section of a bare necrotic cortical plate of the upper jaw (1) of patient S. in the area of the missing 22, 23, 24 teeth (2) before the operation.

FIG. 2 shows a fragment of a necrotic cortical plate of the upper jaw bone (3) and granulation (4) removed from patient S.

2. Patient K., 47 years old, complained of pain in the lower jaw with irradiation along the 2nd branch of the V pair of cranial nerves on the left, general weakness, a defect in the oral mucosa with exposure of the jaw bone tissue and suppuration from the fistulous passage in place of the missing 37 tooth. From the anamnesis, it was established that the patient was observed by an oncologist with a diagnosis of "Prostate cancer, T2N1M0, condition after complex treatment (radiation, bisphosphonate therapy): progression to the region of the jaw bones, spine, stabilization of the process." The patient took 40 mg of zoledronic acid intravenously once every 2 months for 2 years. Treatment. Under infiltration and conduction anesthesia Sol. Ultracaini 4% with adrenaline 1: 100,000 patient K. underwent surgery with the removal of necrotic bone tissue for bisphosphonate osteonecrosis in the region of the body and the branch of the lower jaw on the left (Fig. 3).

During the operation, the postoperative bone cavity with a diameter of 49 mm is filled with a mixture of honsuride, riboflavin and hyaluronic acid, introduced into the composition of a heliokomposite, cured after being placed in a wound under the influence of ultraviolet rays with a power of 450 mW with a wavelength of 450-470 nm for 40 seconds. As a result, a reliable wound sealing was achieved and an acceleration of reparative osteogenesis was ensured, which was confirmed by the results of further clinical observation. Clinical observation showed that in the postoperative period the patient had no pain and swelling of the peri-maxillary soft tissues. A dynamic survey X-ray examination within 1-4 months after the operation revealed accelerated healing of the operated area of osteonecrosis, which was filled with formed young bone tissue with a density of 475 Hounsfield units 4 months after the operation (Fig. 4).

FIG. 3 shows an orthopantomogram of patient K., performed before the operation, on which foci of destruction and necrosis of bone tissue in the region of the body (5) and branches (6) of the lower jaw on the left are clearly visible.

FIG. 4 shows an orthopantomogram of patient K., performed 4 months after surgery with the removal of necrotic bone tissue for bisphosphonate osteonecrosis, which shows a successful restoration of bone density in the area of the body (7) and branch (8) of the lower jaw on the left.

Thus, as a result of the application of the proposed method, acceleration of reparative osteogenesis in bisphosphonate osteonecrosis is ensured, bone repair occurs with the formation of a full-fledged trabecular structure, completely identical to the native bone, there is no immune response even in large bone wounds, reliable wound sealing is achieved, excluding infection.

Claims (1)

A method for accelerating reparative osteogenesis in bisphosphonate osteonecrosis, including the use of honsuride, characterized in that the dilution of honsuride in riboflavin and 2% hyaluronic acid is carried out, followed by the addition of the resulting mixture to the heliocomposite at the rate of 40 mg of honsuride per 20 mg of riboflavin, 2% hyaluronic, 40 mg acid and 120 mg of a heliocomposite, introducing the resulting composition into the wound and curing it for 40 seconds with a 450 mW phytopolymerization lamp with a wavelength of 450-470 nm.

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