Healing of meniscal repairs is mainly dependent upon tear location as only the outer 10–25 % of the meniscus receives direct blood supply from the perimeniscal capillary plexus (PCP) [10]. This plexus is supplied by the lateral, medial, and middle geniculate arteries and originates in the capsular and synovial lining of the joint. Nutrient and waste exchange for cells in the inner portion of the meniscus relies on diffusion through the synovial fluid [11]. Blood supply is critical for healing success as the presence of growth and clotting factors simulates the repair process [12–14]. It has been shown that when exposed to these factors, particularly platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-β), and fibronectin, meniscus fibrochondrocytes are stimulated to proliferate and produce extracellular matrix [15–17].

When a tear occurs in the peripheral portion of the meniscus, a fibrin clot forms which contains inflammatory cells. The PCP then infiltrates the fibrin clot, delivering stem cells and growth factors to aid in the differentiation and growth of the fibrochondrocytes [18, 19]. Some of the growth factors that have been implicated in meniscus healing are PDGF, TGF-β, insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) [19–21]. In an investigation comparing the effect of bFGF, IGF-I, PDGF, and TGF-β on protein and proteoglycan production in bovine meniscus tissue explants, Imler et al. found that all four increased cellular production, with TGF-β being the most potent stimulator [22]. Inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1), on the other hand, have been shown to have a deleterious effect on fibrochondrocyte proliferation in vitro [23]. The expression of other molecules, such as the antiangiogenic factor endostatin, also may limit the regeneration capacity of the meniscus [24].

Mechanically stimulating the damaged tissue provides an injury response, potentiates vascularity, and is one of the simplest ways to favor healing of the meniscus. The most common techniques utilized are rasping (Fig. 11.2) and trephination. These methods create radially oriented channels to theoretically induce vascular and cellular migration from the periphery to the repair site. Ochi et al. studied the effect of rasping on the presence of TGF-β, PDGF, interleukin-1-alpha (IL-1α), and proliferating cell nuclear antigen (PCNA) on the femoral surface of the menisci following rasping [17]. They found that levels of IL-1α, TGF-β, PDGF, and PCNA on the rasped surface area all reached their peak within 14 days after surgery. Many studies have reported improved healing rates of meniscus tears treated with mechanical stimulation as compared to without [25–27].

Exogenous fibrin clot was one of the first substances studied to aid in the healing of meniscal tears. In 1985 Weber et al. demonstrated that rabbit meniscus fibrochondrocytes proliferate and produce matrix proteins when exposed to the mitogenic factors contained in a wound hematoma [15]. Based upon this initial work, Arnoczky et al. studied the effect of exogenous fibrin clot application on the healing rate of meniscal tears in the avascular region of canines [10]. At 3 and 6 months postoperatively, they reported that all the defects had filled with fibrocartilage-like material. Clinical case series utilizing fibrin clot followed, with van Trommel et al. reporting healing on second look arthroscopy in all patients following repair of peripheral posterior-lateral meniscus tears supplemented with fibrin clot [28]. In a series of 153 meniscus tears with or without concomitant ACL tear, Henning et al. reported a healing rate of 92 % when treated with exogenous fibrin clot versus 59 % for those treated without fibrin, concluding that isolated meniscus tears heal significantly better with the addition of the exogenous agent [29]. In a randomized trial comparing conservative therapy, arthroscopic suture repair with access channels, arthroscopic minimal central resection with intrameniscal fibrin clot and suture repair, and arthroscopic partial meniscectomy, Beidert found 75 %, 90 %, 43 %, and 100 %, respectively, of normal or nearly normal exam and MRI at final follow-up [30]. In other words, the group receiving meniscus repair and fibrin clot application had the lowest clinical and imaging scores. Each group in this study, however, included 12 or fewer patients (with the fibrin clot group consisting of only seven patients), potentially limiting the applicability of this investigation to the larger population.

Platelet-rich plasma (PRP) is an autologous substance that contains concentrations of platelets above physiologic levels (Fig. 11.3). These platelets are a source of PDGF, TGF-β, IGF-1, VEGF, and bFGF, among others, and are thought to initiate a healing cascade leading to angiogenesis, matrix production, and cellular proliferation [31–33].

Ishida et al. performed the most comprehensive basic science and animal investigations to date on the effect of PRP on meniscus healing [34]. Using a gelatin hydrogel (GH) to deliver PRP to rabbit meniscal fibrochondrocytes in vitro, they found that levels of growth factors (PDGF, TGF-β, and VEGF) as well as messenger RNA (mRNA) for biglycan and decorin were all higher in cultures supplemented with PRP as compared to platelet-poor plasma (PPP). The authors then used the same delivery system to treat 1.5 mm diameter defects in the avascular zone of rabbit menisci. At 4 weeks, they found residual presence of the hydrogel, indicating elution of the growth factors from PRP took place over this timespan. Histological scoring of the menisci at 12 weeks showed significantly better meniscal healing in the group treated with PRP-infused hydrogel as compared to the hydrogel with PPP or the hydrogel alone [34].

Another investigation examined the effect of hyaluronan-collagen composite matrices without cells, the composite matrices loaded with platelet-rich plasma, autologous bone marrow, or autologous mesenchymal stem cells (MSCs) to treat 2 mm punch defects in the avascular zone of rabbit menisci [35]. At 12 weeks, the authors reported the untreated defects and cell-free composite matrix groups both had a limited fibrocartilaginous healing response. Interestingly, they found that neither the PRP nor bone marrow-loaded matrices showed histological grading improvement as compared to cell-free implants.

Under the proper conditions, MSCs have the capability of differentiating into a number of different cell lineages and therefore represent a promising option in the augmentation of meniscus repair. There has been documentation of MSCs availability from bone marrow [36] (Fig. 11.4), periosteum [37], adipose tissue [38], and the synovial lining of major joints [39]. In both cartilage and meniscus restoration investigations, they are commonly delivered to the desired treatment area through the use of a cellular scaffold [40, 41].

Meniscus repair is not always possible, particularly in the case of complex tears. Debridement of large tears may lead to meniscal deficiency after debridement. In young patients who are not candidates for arthroplasty, meniscus replacement is an option. Choices for replacement include allograft transplantation, collagen-based scaffolds, and synthetic scaffolds.

Increased levels of inflammatory cytokines are associated with injuries to the knee. These inflammatory cytokines increase enzymatic tissue degradation and suppress matrix biosynthesis [59]. Investigations have demonstrated that IL-1 dose dependently decreases the shear strength of meniscus repair through inhibition of tissue formation at the meniscus repair interface [60–62]. Hennerbichler et al. harvested cylindrical explants from the outer one-third of the medial meniscus in a porcine model. The explants were immediately replaced and the entire specimen was incubated in medium with and without recombinant porcine IL-1. Those cultured in medium with IL-1 showed no discernable repair tissue despite the presence of viable cells [62]. The mechanism through which IL-1 provides its detrimental effects to meniscus healing is not fully understood. Recent evidence, however, has shown that matrix metalloproteinases (MMP) may play a role. McNulty et al. demonstrated that even in the presence of IL-1, a broad-spectrum MMP inhibitor increased the shear strength of meniscus repair sites and enhanced tissue repair at the interface compared to samples without MMP inhibitor [63]. Given these data, the search is underway for the optimal cytokine and/or MMP inhibitor in the attempt to enhance meniscus healing rates.