**12. Surgery and trauma (Autologous fibrin Glue)**

The introduction of fibrin glue in repair techniques started in the beginning of the 20th century. Its main use remains within surgical interventions and undergoes constant modification for better results. Fibrin glue became the predecessor of contemporary PRP treatment [99].

A number of studies show the benefits of fibrin and platelet combined treatment. According to Everts et al., the application of autologous platelet gel and fibrin sealant in total knee arthroplasty lead to "significant postoperative increases in hemoglobin rates, required less allogeneic blood, and had fewer complications during wound treatment", thus showing high efficiency of treatment method [100]. Levy et al. evaluated the hemostatic efficiency of adhesive fibrin in 58 patients (a control group and a fibrin treated group) undergoing total knee arthroplasty. Outcomes were significantly higher blood loss for the control group (24 patients needed blood transfusion versus only six from the treated group) and no ostoperative adverse events in the treated group [101]. Sánchez et al.'s findings show the recovery of 12 athletes treated for total Achilles tendon rupture (six received an association of PRGF), during which repair was completed significantly faster than that of the control group, needed less time to recover range of motion and to resume training [102].

It is estimated that few studies have examined PRP action during treatment of orthopedic trauma [67,103], which shows that common treatment was the combination of PRP with bone graft, bone marrow and various bone substitutes (tricalcium phosphate, hydroxyapatite bioceramics), as well as treatment with human mesenchymal stem cells in an osteoconductive environment (platelet gel application used to increase formation of new bone tissue through modulating and stimulating the healing cell mediators) [67,103-105].

Other studies represent the effect of biological material in the hemostasis after total substitution of the articulation. According to the results of "98 total arthroplasties of the knee, 61 received application of PRP in the intraoperatory period on the exposed tissue and on the closure of the wound at the end of the procedure". Conclusions showed significant acceleration of recovery and better overall mobility and quality of life in PRP treated patients. The reasons for such fast recovery were attributed to the direct PRP application on knee surgery after arthroplasties. This seals the tissue and takes platelets directly to the wound, where the regeneration process starts immediately [106].

PRP may be used on patients with factures or in cases of total arthroplasies. With the intro‐ duction of new cement–free implants, the use of PRP between the implant and the bone might speed up the osteointegration process and improve the implant fixation [38].

#### **13. Conclusion remarks**

**10. Anterior Cruciate Ligament (ACL)**

184 Immunopathology and Immunomodulation

were found in any of the treated athletes [65,98].

**12. Surgery and trauma (Autologous fibrin Glue)**

use of PRP in human muscle injuries [38].

94,95].

platelets (40%)" [93].

**11. Muscle**

As a result of the growing popularity of growth factor treatment techniques, PRP treatment applications have increased for both soft and bone tissue therapies. Several studies include positive results from such treatments. Repair of ligament injuries was tested by Sánchez et al., resulted in better healing outcomes and fewer complications after applying PRP to 100 patients with ACL reconstruction [93]. Fixation of the PRPG graft was studied by Radice et al. and the results were evaluated using MRI images of the interior of the ACL graft and concluded a 48 % faster and completely homogenous repair of the PRPG graft in the experimental group [83,

Controversial opinions are shared on the application of PRGF/PRP in the reconstruction of the ACL and posterior cruciate ligament (PCL), such as the degree of effectiveness in the integra‐ tion of the graft into the bone tunnel and rates of graft maturation [29,94,96]. A statistically significant difference (p = 0.023) was found during stimulation of both ACL graft maturation and ACL graft-bone healing with PRP application [93]. After histological assessment of the ACL grafts with and without PRP, Sanchez et al. found "a significantly better maturity index for ACL grafts (12 pts vs. 14 pts, p = 0.024), and more newly developed synovial tissue enveloping the platelet treated grafts (77% of cases) compared to the control grafts without

The use of PRP in muscle injury treatment still hasn't been studied thoroughly in humans [74, 97]. There are a number of studies on the effects on muscle tissue. For instance, Shen et al. stated that the inflammatory phase of skeletal muscle healing was controlled by growth factors, macrophages, and COX-2 pathway products [90]. According to Sánchez et al. "the clinical benefits of the ultrasound-guided application of growth factor in physical therapy, electro‐ therapy, and isometric exercise" for athletes include "a decrease in pain and swelling, a complete recovery of functional capacities before the expected time, and regeneration of the muscle tissue according to ultrasound". No evidence of fibrosis and no recurrence of injuries

Nevertheless, there still have to be more studies necessary to define the efficiency of PRP in acute muscle injury treatment and to create adequate protocols for administration. The main reason is the insufficient number and low methodological quality of the current studies on the

The introduction of fibrin glue in repair techniques started in the beginning of the 20th century. Its main use remains within surgical interventions and undergoes constant modification for better results. Fibrin glue became the predecessor of contemporary PRP treatment [99].

In the last few years various methods are applied in the use of PRP during treatment in different orthopedic disease and sports trauma. They allow improvement of local biological condition and regeneration of different types of tissues. Without doubt the use of PRP is absolutely a treatment option. According to Werner and Cramer the platelet is the most important cell for the repair processes of the body [74].

Recently, scientific research and technology have presented a new perspective concerning the understanding of "orthobiologic" treatments and the healing process of lesions [38].

PRP treatment is widely applied in the last ten years, especially for stimulating coagulation. A number of studies show that platelets demonstrate other functions, too. They are connected to liberating bioactive proteins and growth factors. The bioactive proteins as well as the growth factors improve tissue regeneration and the process of healing. PRP is the first true biologic therapy that has hit orthopedics by storm. Its ease of use and generally high safety profile has made it a preferred option for the most of the physicians and their patients worldwide. When trauma of musculoskeletal system injuries occur healing takes longer periods of time, and frequently they do not recover completely. Fast and effective recovery is of particular impor‐ tance for athletes. That's why all healing methods that accelerate the recovery process are fundamentally important. Many different pathologies can be treated with PRP.

The administration of PRP in athletes has been gradually introduced in everyday patients. This has become another option for treatment in addition to conservative options. A number of surgical manipulations can influence results in PRP treatment, such as grafts, medication, and physical therapy.

"Following recommendations of the International Olympic Committee (IOC), the local applications of PRP have been used in the treatment of mild to moderate lesions with no surgical indication, or during surgery" [107].

Main indications are acute and chronic wounds, pseudarthrosis, ligament and muscle injuries, some tendinopathies, osteoarthritis, chondral injuries. Almost all the surgeries carried out since 2007 have used PRP, whether in gel or liquid form [108].

PRP represents an autologous biological material as its action is directly related to general clinical conditions of the patient. The particular reason for the appearance of lesions is important in order to select an appropriate treatment method and technical application. However, standardization in PRP protocols and long-term follow-up should clarify some of the questions regarding the durability of these procedures and any possible modification that should be done to achieve better results.

Various additional new studies are necessary to further improve the results of PRP application in different pathologies. This will help with understanding the different stages of the healing process and demonstrate the potential of PRP treatment in everyday patients.
