The tissue engineering approach has been shown to have great potential for tissue regeneration and tissue repair. An autologous fibrin clot derived from peripheral blood has been used to accelerate meniscal healing for more than 20 years. In 1988, Arnoczky et al. [7] reported that a fibrin clot derived from peripheral blood improved meniscal healing in dog experiments. The fibrin clot is reported to be effective for tissue regeneration because of its biological characteristics [7–10]. It is known that the fibrin clot contains a variety of bioactive factors including several GFs and can act as a scaffold to fill the defect. In addition, the fibrin molecules of the fibrin clot serve both as storage and a release system for these bioactive factors. The major advantage of using a fibrin clot is the lack of allogenic or xenogeneic factors. Moreover, the plasticity of the prepared fibrin clot allows adaptation to various tissue topographies during implantation. The fibrin clot can be made easily in the operating theater at low cost.

For patients with meniscal tears in the avascular zone, we use an autologous fibrin clot derived from bone marrow instead of a fibrin clot made from peripheral blood. This is because we have confirmed that a bone marrow-derived fibrin clot contains more GFs such as vascular endothelial GF (VEGF), hepatocyte GF (HGF), and basic fibroblast GF (bFGF) than a peripheral blood-derived fibrin clot, and a bone marrow-derived fibrin clot has also been proven to have more potential for fibroblast proliferation than a peripheral blood-derived fibrin clot. This indicates the efficacy of a bone marrow-derived fibrin clot for tissue regeneration and clinical use (unpublished data). Our own unpublished preliminary results using a bone marrow-derived fibrin clot for meniscal repair have shown good clinical results at an average of 1 year postoperatively. Although further studies with longer-term follow-up are necessary to support a definitive conclusion, we believe that using a bone marrow-derived fibrin clot for meniscal repair is a reasonable and promising treatment option for patients with meniscal tears in the avascular zone.

GFs are polypeptides that have specific effects on the activity of target cell by binding to the specific receptors of the cell. The possible effects include a change in cell’s gene expression, proliferation, differentiation, migration, and adhesion. These are all critical functions of cells, and employing GFs as biologics can provide positive outcomes. Platelets are small bodies, cytoplasmic fragments of megakaryocytes, without a nucleus that are found in the peripheral blood. PRP is an autologous plasma with a platelet concentration of 106 platelets per μl which is much higher than the baseline that is around 2 × 105 platelets per μl in a volume [11–13]. Platelets have vital roles in the wound healing with various proteins in the α granules [11, 14, 15]. PRP has been extensively studied for their potential therapeutic effect [16–19].

PRP is a critical source of native cytokines and GFs, as well as it contains other bioactive molecules, including but not limited to adhesive proteins (fibrin, fibronectin, and vitronectin), clotting factors, fibrinolytic factors, proteases, and antiproteases [20]. PDGF, TGF-β, FGF, IGF, VEGF, and EGF are among the GFs present in PRP [20]. Thus, use of PRP can provide increased potential to augment tissue healing [11–13]. PRP is intrinsically safe due to its autologous source, cannot cause mutation since PRP-derived GFs bind to the external surface of the cell membrane, and do not enter the cell or cell nucleus [13]. PRP is prepared from anticoagulated blood [21] and activated by clotting. Calcium chloride, thrombin, fibrin, and collagen type I are among the platelet-activating agents [22]. Platelets secrete most of the stored GFs for the first 10 min. Almost all of the stored GFs are secreted in the first hour. Then, the platelets produce more GFs for around 1 week [12, 13].

Since PRP is an autologous biologic, it is donor dependent, and there are differences due to different donors [23]. Moreover, different commercially available systems (e.g., from Biomet, Arthrex, Arteriocyte, Harvest Technologies, Medtronic, and MTF Sports Medicine) provide PRPs that are different in the number of platelet and blood cells [11, 22, 24, 25]. In a study [26], it was demonstrated that three different commercial systems provide different platelet, GF, white blood cell and red blood cell concentrations, and platelet capture efficiency. These are important source of variation in the application outcome. Figure 58.3 illustrates the important factors affecting the outcomes of PRP application including donor-based differences, timing and volume of PRP, platelet concentration, delivery strategy, and preparation method.

The evaluation of the clinical biologic treatments can be done both with subjective outcomes and objective outcomes [27]. The clinical outcomes are the subjective including International Knee Documentation Committee (IKDC) score, Tegner Lysholm Knee Scale score, survey tools, visual analog scale, Victorian Institute of Sports Assessment, and Western Ontario and McMaster Universities osteoarthritis outcome (WOMAC) score, while the objective assessment can be done by histology, second-look arthroscopy, and medical imaging modalities, e.g., magnetic resonance imaging and ultrasound, and with the use of specific biomarkers for each GF or cytokine [27].

Effects of PRP release from collagen matrix on human meniscus cells in vitro were found to be that PRP was beneficial compared to peripheral blood to increase the growth and upregulate gene expression of collagen type I, elastin, and aggrecan [25]. The study suggested that PRP may provide a small benefit for minor meniscal defects if PRP can be accumulated. Another in vitro study showed that PRP treatment increases the 30-kDa fibronectin fragment-induced synthesis of a number of pro-inflammatory chemokines and matrix metalloproteinases by human meniscocytes and articular chondrocytes [28].

In a study with rabbit meniscocytes [29], the presence of PRP in the cell culture medium can promote cell proliferation and extracellular matrix synthesis. The mRNA expression of biglycan and decorin was upregulated while the expression of collagen type I remained the same when compared to that of with the meniscocytes cultured in medium with platelet-poor plasma or 1% fetal bovine serum. In the same study, in vivo effects of PRP were also investigated in a rabbit model. Full-thickness defects in the avascular region of meniscus showed histologically better repair at week 12 when the defects were filled with PRP incorporated in a hydrogel as compared to treatments with platelet-poor plasma incorporated in a hydrogel or hydrogel alone [29]. In a rabbit model for meniscus repair, it was reported that FGF-2 within a gelatin hydrogel significantly increased the cell proliferation and enhanced meniscal repair [30]. However, in another rabbit model study, PRP and BMP7, alone or together, did not significantly promote meniscus regeneration in avascular defects in vivo [31]. In a recent rabbit model study [32], horizontal medial meniscus tears were treated with a single injection of leukocyte-rich PRP and evaluated histologically up to 6 weeks. However, no significant differences were found between the PRP-treated group and the control group.

In a recent arthroscopic meniscus repair study [33], the differences between outcomes of the meniscus repair with and without PRP were reported to be indistinguishable in terms of functional outcome measures as well as the reoperation ratio and the proportion of patients who returned to their regular activities: sports and work. It was discussed that the study being underpowered and performed with a small sample size, a difference between groups with and without PRP augmentation, might not be detected [33].

The effects of PRP on the meniscal healing were studied in a case-control clinical study with young patients [34]. The injection of 5 ml of PRP directly into the lesion with horizontal cleavage meniscal tears following the standard open meniscal repair procedure was carried out. Clinical outcomes were reported at midterm follow-up to be only slightly improved by the in situ PRP injection [34]. In another study, one patient with a meniscal tear and knee pain was treated with percutaneous injections of a mixture of adipose tissue-derived stem cells, PRP, and hyaluronic acid (HA) and calcium chloride [35]. Even though there was no clinical improvement, the patient reported a significant decrease in pain only after injections.

PRP has been evaluated in vitro, in vivo, and clinically for other parts of the body other than meniscus, including but not limited to cartilage [36–38], rotator cuff [39–42], intervertebral disk [43–46], osteochondral tissue [36, 47, 48], muscle [49–51], ligament [52–54], and tendon [55–57]. The reported outcomes are very different and sometimes contradictory.

The effect of a combination of PRP and HA in osteoarthritis therapy was tested both in vitro and in vivo [58]. It was shown that osteoarthritis-related chemokines and cytokines can be suppressed, cartilage regeneration can be promoted, and an anti-inflammatory effect can be obtained [58]. PRP improved the patellar tendon harvest site healing in a randomized controlled trial [59]. A systematic review in 2012 [60] concluded that for the arthroscopic rotator cuff repair, PRP does not affect the retear rates or shoulder-specific outcomes. However, a systematic review in 2013 [61] analyzed the in vitro, preclinical, and clinical studies regarding the intra-articular injections of PRP. It was reported that PRP injection showed an overall benefit in preclinical studies for the healing of joint tissues, and among the high-quality clinical studies (only a few), PRP treatments showed only a benefit limited over time.

The systematic review and meta-analysis regarding the clinical benefit of PRP in orthopedics reported by Sheth et al. [62] revealed that the use of PRP is not significantly beneficial until 24 months across the randomized trials or prospective cohort studies. A small trend supporting the use of PRP exists but with wide confidence intervals. It was also reported that the literature lacks the standardization of study protocols, PRP preparations, and outcome measures [62, 63]. Nourissat et al. [64] also reported that there is no evidence-based medicine data that supports the use of PRP in arthroscopic surgery.

In an in vivo study with rabbits [65], circular defects were created with a punch in the avascular regions of menisci; the defects were treated with hyaluronic acid-collagen matrix either empty or with PRP or with mesenchymal stem cells. It was reported that cell-free treatments were not resulted with tissue healing. In a later study [66], the performance of mesenchymal stem cell-loaded scaffolds was tested in a longitudinal meniscal tear model. It was reported that for a successful avascular zone healing, stem-cell differentiation is a must; however, with the conditions in the study, the repair tissue was meniscus-like with a certain level of biomechanical strength. However, in the same study, treatments with PRP alone in the matrix did not provide any significant benefit [66]. It should be noted that PRP was not incorporated with cells in both studies [65, 66]. It would be interesting to see how PRP would affect the cells for the tissue healing. An in vivo study with mice [67] showed that PRP pretreatment of human articular chondrocyte-seeded scaffolds provides more cell attachment compared to ones without PRP pretreatment. It was concluded that PRP pretreatment may enhance the surface properties for cell attachment, and it can be used for meniscus tissue engineering [67].

Another use of PRP is to replace the fetal bovine serum (FBS) in cell culture [68]. It was demonstrated in an in vitro study that 10% or 20% PRP can be used instead of 10% FBS supplementation to standard cell culture medium to cultured human meniscocytes with same proliferation and gene expression level [68]. This makes it possible to avoid the clinical concerns regarding the use of FBS in cell culture medium.

Fibrin clot derived from bone marrow or peripheral blood, as well as PRP can augment tissue healing. Fibrin clot and PRP contain a range of bioactive components including GFs. Fibrin clot does not have allogenic or xenogeneic factors, and its physical form fits to various tissue topographies during implantation. The clinical benefit of PRP is not yet agreed by all in the literature, and there are opposing views on the outcomes of PRP treatments; this might be due to the absence of standardization of the evaluation of the outcomes of the biological treatment studies, as well as the study designs. Due to the life-span of platelets and half-life of released GFs, the presence of GFs may not be sustained and controlled with a single PRP injection. Thus, PRP injections can be repeated on a regular basis, or their release can be controlled within a matrix/hydrogel. Besides, it is also required for a better understanding to quantify the amount of GFs released and also the duration of their biological activity. It should be also noted that GFs interact with cells and modulate cells’ function. For this reason, it can be more beneficial if native and/or recruited cells need to be at the site where PRP is applied to interact with the released proteins from platelets. Additionally, for the proper evaluation of the PRP treatment, the study must be very well designed with all necessary sample groups, which was not present in some studies in the literature.

It should be also noted that the secretion of GFs is an important step. The GFs in the α granules of platelets are not complete unless they are soluble. During the GF secretion through the cell membrane, the GFs get completed by the inclusion of histone and carbohydrate side chains. Thus, no GFs will be secreted from platelets if platelets are damaged or died during the PRP preparation, and in such case, the outcome of using PRP will not be encouraging.