Application of platelet-rich plasma loaded with antibiotics systems in treating infected bone defects

Infected bone defect (IBD) is one of the most serious complications in orthopedics. The treatment of IBD is a clinical challenge for orthopedic surgeons, and the available treatment is very limited. Dr Jun Fei and his colleagues from the Department of Emergency Medicine of Daping Hospital, have been explored application of platelet-rich plasma (PRP) in the treatment of IBD. Their results suggest that using PRP loaded with antibiotics system (PADS) to treat infected bone defect can effectively increase the cure rate of IBD and reduce the rate of recurrent infection. It is a new treatment method for IBD.

Infected bone defect (IBD) is a serious complication in orthopedics. IBD often arises from high-energy trauma, osteomyelitis debridement, and implant infection. When infected bone defects appear, infection is difficult to completely eliminate, especially when it is accompanied by large bone defects, because the existence of bone defect provides better reproduction conditions for bacteria, and reduces the human body’s immune ability to clear bacteria. The vicious circle of these factors makes IBD one of the most difficult problems in orthopedics.

In the past decades, platelet rich plasma (PRP) has been an important achievement in tissue engineering. It is rich in a variety of growth factors, which can significantly accelerate and promote the regeneration of new bone, showing very broad potential for clinical application. Especially in the last 10 years, PRP has been widely reported in the field of orthopedics. Therefore, Professor Fei and colleagues are researching whether it might be feasible that PRP be used to treat infected bone defect.

Biofilm formation is the key
If the infection is serious and is not well controlled in the early stage, the bacteria at the infected site will form a biofilm after 72 hours of infection. Some bacteria can even penetrate the cell membrane and enter the normal cells of the body. Biofilm coverage and cell protection mean these bacteria can escape from the treatment of antibiotics and the killing function of the human immune system, which makes the bacteria colonise the body for longer and become a chronic infection. Patients with recurrent disease also show unsatisfactory treatment effects.

The formation of biofilm does not mean that the treatment fails or cannot be cured, but the formation of biofilm increases the difficulty of treatment. Standard treatments for infected bone defects include debridement of necrotic bone fragments, local and systemic use of antibiotics, and bone graft reconstruction.

Membrane induced technology (Masquelet) has become a new treatment for infected bone defects. Early studies have proved that the Masquelet technique has achieved good results in the treatment of IBD, and it has gradually become the standard treatment. Masquelet technology can clear infection in stage I through debridement and bone cement application. For chronic infection with biofilm formation, infection can be well controlled through debridement and removal of implants. High concentration antibiotics in local bone cement can kill bacteria and inhibit biofilm formation. At the same time, the volume of bone defect is filled with cement to reduce the risk of infection.

But whether it’s the traditional treatment or Masquelet technology, these treatments are very time-consuming (often taking months to years), and do not always produce satisfactory results. This is largely due to the difficulty of infection control, which leads to chronic infection and delayed bone remodelling. Recent studies have shown that bacteria attached to implants may be a potential source of infection in surrounding tissues. Therefore, there is an urgent need for an effective method that can not only eliminate infection, but also promote the formation of new bone to shorten the treatment cycle and improve the treatment effect. In the exploration of treatment, Professor Fei found the potential value of PRP in the treatment of IBD.

Platelet rich plasma
PRP is the small volume plasma or platelet concentrated plasma obtained after centrifugation, which is higher than the baseline level of whole blood platelet concentration. There is no unified standard or requirement for platelet concentration in PRP because of different sources of whole blood and different production methods. Generally, the platelet concentration in most PRP is 3-10 times higher than that found in normal blood.

The application of PRP can regulate the inflammation around the wound and the process of tissue repair. There are a lot of growth factors in α granule of PRP. PRP can release a large number of cytokines and chemokine after activation. These cytokines play an important role in regulating wound inflammation. Chemokine can make a large number of inflammation and stem cells migrate to the wound site, thus regulating the tissue wound repair. Platelet releases α granule after activation and a lot of growth factors contained in PRP can promote tissue regeneration. These growth factors are bioactive substances, and their release near the wound can produce strong bioactive effects to accelerate tissue repair by promoting inflammation, cell migration and cell proliferation and differentiation.

Professor Fei and colleagues found that PRP has certain antibacterial ability in the treatment of tissue defect. The following antimicrobial tests also confirmed this effect. This antibacterial effect mainly comes from the antimicrobial peptides in PRP and leukocytes, which have the ability to kill bacteria, but this antibacterial ability is too weak to treat complex infections in clinic. It was this ability which triggered new research for Dr Fei and his team.

PRP loaded with antibiotics
Our research team has been working hard to find materials which possess double properties including promoting wound healing alongside powerful antibacterial ability. In subsequent studies, it was found that PRP combined with antibiotics (PADS) can greatly enhance the antibacterial activity of PRP, and this antibacterial activity can last for 72 hours. At the same time, the healing activity of growth factors in PRP was not disturbed by loading antibiotics. The existence of this antibacterial activity can ensure the application of PRP in infected diseases.

For PADS in the treatment of IBD, the antibacterial ability of PRP can make the local antibiotics more than ten times that of MIC and can last for 72 hours, which can inhibit the formation of bacterial biofilm. The growth factors in PRP can promote wound healing, increase angiogenesis around the wound, and further improve the condition of soft tissue. In addition, the angiogenesis can also improve the ability to clear and kill pathogens. Moreover, Fibrin in PRP can form a three-dimensional structure when it is activated. This structure in PRP can provide a scaffold for cell proliferation and growth, thus promoting tissue repair.

What about the patient?
Most patients are concerned about the curative effect, cost, complications, surgical risks etc. Professor Fei demonstrated that PRP loaded antibiotics combined with Masquelet technology in the treatment of patients with IBD showed an improved treatment effect. By using PRP loaded with antibiotics system in stage I and II operation, the recovery time of patients was significantly shortened. At the same time, because PRP comes from autologous blood, it has no risk of immune response and disease infection. After the application of PRP, it can significantly reduce the overall treatment cost of patients, and the treatment technique is simple, so it will not increase the additional operation time. PRP loaded with antibiotics shows a good therapeutic effect, and has broad clinical application prospects.

‘Both in vitro and clinical trials have shown that PADS combined with Masquelet technology can be used as an improved treatment for IBD,’ Professor Fei said. To improve the cure effect of IBD and reduce the recurrence rate of infection and disability rate is essential work for orthopedic doctors, because it can greatly reduce the pain of patients and the risk of amputation and disability caused by infection.

Could this become a standard therapeutic tool for curing infected bone defect?
The role of PRP in tissue repair has been proven in various fields, and PRP loaded with antibiotics shows its potential value in the treatment of infected bone defects. However, due to the lack of standard preparation methods, there are different reports on the treatment of PRP, and our future work will verify the effectiveness of this method in clinical work. In addition, the sustained antibacterial and healing ability of PRP is also very important. Our research seeks to further improve the system to achieve better therapeutic effects.

S, W., Y, L., S, L., J, Y., R, T., X, L., L, L. & J, F. 2020. Platelet-rich plasma loaded with antibiotics as an affiliated treatment for infected bone defect by combining wound healing property and antibacterial activity. Platelets, 1-13. TANG, R., WANG, S., YANG, J., WU, T. & FEI, J. 2020a. Application of platelet-rich plasma in traumatic bone infections. Expert Rev Anti Infect Ther. TANG, R. H., YANG, J. & FEI, J. 2020b. New perspectives on traumatic bone infections. Chin J Traumatol, 23, 314-318.

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