The role of biomaterials in the treatment of meniscal tears

Biomechanics and function

The menisci are fibrocartilage structures, composed mainly of type 1 collagen, that sit on top of tibia, Fig. 1.

The lateral meniscus (e) is a C-shaped structure that covers approximately 80% of the lateral tibial plateau whereas the medial meniscus (c) is a U-shaped structure and covers only 60% of the medial tibial plateau. The menisci are relatively avascular with only 10–30% of the peripheral region of the medial meniscus and 10–25% of the lateral meniscus being vascular (Arnoczky & Warren, 1982). Based on its vascularisation, the menisci can be divided into three zones: the red-red vascular zone (outer peripheral region), the white-white avascular zone (inner region) and the red-white zone which lies between of the two other zones and has characteristics of other two zones. The red vascular region is thick and convex and attaches to the capsule of the joint whereas the white-white inner region is thin, concave and is a free edge unattached to the joint.

The menisci effectively deepen the tibial plateau and allow smooth articulation between the tibial and femoral condyles and the transmission of loads across the tibiofemoral joint. In full knee extension, the medial meniscus transmits approximately 50% of the load on the medial compartment, while lateral meniscus transmits approximately 70% of the load in the lateral compartment (Walker & Erkman, 1975). As knee flexion increases the amount of load transmitted to the lateral meniscus increases such that when the knee is flexed beyond 75°the entire load that passes through the lateral compartment, is transmitted by the lateral meniscus (Walker & Erkman, 1975). For the medial meniscus the increase in load transmission as the knee flexes is less apparent (Walker & Erkman, 1975). When the meniscus is intact, the load is well distributed across the tibiofemoral compartment; however when part or the entire meniscus is removed there is considerable alterations to load distribution such that there is a decrease in the contact area and increases in peak contact forces (Bedi et al., 2012; Lee et al., 2006; Ihn, Kim & Park, 1993).

Meniscal tears

Meniscal tears are one of the most common intra-articular knee injuries (Clayton & Court-Brown, 2008; Majewski, Susanne & Klaus, 2006) and is typically the result of an axial loading and rotational forces which result in a shear load on the meniscus (Browner, 2009). This may be a result of a traumatic event or cumulative stress leading to degenerative tears. The medial meniscus is more often injured than the lateral (Majewski, Susanne & Klaus, 2006); however, lateral meniscal tears are more often associated with acute ACL tear (Bellabarba, Bush-Joseph & Bach Jr, 1997). Although there is no uniformly accepted classification of meniscal tears, the classifications typically involve a description of the tear pattern and location. Common tear patterns that typically originate from traumatic events include longitudinal, bucket-handle, and radial tears (Greis et al., 2002). Whereas horizontal, flap and complex tears are typically seen in older adults and due to cumulative stress resulting in degeneration (Greis et al., 2002). The location of the tears may be classified based on the zone classification system purposed by Cooper, Arnoczky & Warren (1990) in which the menisci are divided into three radial zones (anterior, medial and posterior) and four circumferential zones (meniscosynovial junction or periphery, outer third, middle third and inner third of the menisci) (Fig. 2).

In a similar fashion to the zone classifications, tears may be graded as partial or full-thickness tears or using a grading scheme 0–III in which 0 indicates a normal intact menisci and III a full-thickness tear (Cooper, Arnoczky & Warren, 1990; Pihl et al., 2017).

Available treatment options

Meniscal tears account for a significant portion of surgical procedures performed by orthopaedic surgeons, the patient experiences significant pain and sometimes complete disability from these tears and resulting procedures (Berthiaume et al., 2005). The surgical procedures involved in the treatment of a meniscal tear may include a partial or full meniscectomy or a meniscal repair. The meniscectomy procedures involve either part or all of the damaged meniscus being removed which in turn leads to higher rates of osteoarthritis in subsequent years. Surgical treatment of meniscal injuries has undergone a number of developments over the past two decades, moving from open arthroscopic surgery; from total to partial meniscectomy and adding novel treatments; such as repair using a variety of devices, materials, transplants, collagen implants or xenografts (Kim et al., 2013; Jiang et al., 2012; Grogan et al., 2017; Baek et al., 2017). If meniscectomy takes place or insisted upon, this procedure is mainly due to changes in load distribution across the articular cartilage as studies have shown that following total meniscectomy peak contact pressures increase by 253% and 165% following partial meniscectomy (Lee et al., 2006; Baratz, Fu & Mengato, 1986; Beamer et al., 2017; Van Egmond et al., 2017). Following meniscectomy, there is also evidence of reduced muscle strength, altered gait patterns and clinical outcomes (Hall et al., 2013; Hall et al., 2014; McLeod et al., 2012; Sturnieks et al., 2008a; Sturnieks, Besier & Lloyd, 2011; Sturnieks et al., 2008b; Salata, Gibbs & Sekiya, 2010; Scholes et al., 2017). For these reasons, there are an increasing number of interests in performing meniscal repair. What needs to be remembered is that not all meniscal tears are suitable for repair, and thus other treatment options such as meniscal replacement and regeneration are of considerable interest when a surgical intervention is necessary to improve any pain and symptoms.

Tissue engineering using biomaterials

Of late, tissue-engineering and cellular biomaterial interactive concepts have been introduced to develop cellular-based reparation for cartilage regeneration (Temenoff & Mikos, 2000). The type of cell used to engineer cartilage is critical as a future goal of biomaterial development. Various cell populations that have been investigated for these roles include: chondrocytes (King et al., 2017; Chen & Cheng, 2006), mesenchymal stem cells, bone marrow stromal cells and perichondrocytes (Bruns et al., 1998). The choice of biomaterial is critical to the success of tissue engineering approaches for cartilage repair. The concept of ‘tissue engineering’ was first introduced and postulated by Green Jr (1977) where chondrocytes grown ex vivo could be transplanted into a region of tissue defect. Recently, tissue and biomaterial engineering concepts have been initiated to develop cellular based approaches for tissue repair (Freed et al., 1993). Typically, the process for engineering tissue involves the isolation of chondrocytes which are then seeded into a biocompatible matrix or scaffold and finally cultivated for implantation into the defected region. A large variety of biomaterials, natural and synthetic, have been employed as potential cell-carriers for tissue regeneration. The most common naturally occurring materials include type I and type II collagen-based biomaterials. Furthermore, some of the contrasting synthetic approaches include: polyglycolic acid or poly-L-lactic acid or other various composite mixtures (Chen & Cheng, 2006). In essence, an ideal candidate biomaterial would be a cell-carrier substance which closely mimics the natural environment in the surrounding matrix—as given by the definition of a biomaterial.

Regenerative approaches to meniscus repair occurs in a series of precise stages. It is typically understood that the low cellularity (endogenous meniscus cells and meniscus progenitors) (Mauck & Burdick, 2015), the dense ECM, poor vascularisation potential and the inflammatory responses typically linked to meniscus wounds all contribute to the success or failure of the meniscus healing and regeneration alone. This success of healing process is without a biomaterial introduced into the site. Based on these principles, the potential use of a biomaterial to develop and deliver a viable solution requires thought around this repair process.

Biomaterials are typically promoters of tissue repair through provision of scaffold layers for cellular attachment and growth and differentiation further acting as a vehicle for protein and gene transfer to regenerate functional tissue approaches (Chen, Zhang & Wu, 2010). Biomaterials in this area should have several properties to support viable repair. Typically, this is achieved through:

1. The material must act as a support structure for cell lines (i.e., cells that are seeded in vitro are compatible, adhere to the material if required or certain cell lines are not required; filtered out). For meniscal repair the biomaterial must provide appropriate biomechanical functions after implantation to shield cells from damaging or compressive forces;

2. Possess sufficient mechanical strength to protect the surrounding cells (cells should be mechanically stable i.e., cell attachment is maintained). For meniscal repair the biomaterial must maintain their shape and integrity, mechanical stability and strength for the defect area in question until new host tissue has been regenerated. Furthermore, it may be important to provide biological and mechanical context for cell differentiation, proliferation and attachment when a biomaterial is introduced into the knee. For example, it is now very well understood that cells are influenced by the local external environment including the adhesive and biophysical properties (Engler et al., 2006);

3. Withstand in vivo forces during the joint movement operation (mechanical and structural stability of the biomaterial in the meniscus area needs to be able to withstand compressive and tensile forces (these forces have been aptly described in Paschos et al. (2017));

4. Bioactivity should be provided to accommodate cellular attachment and cellular migration (the biomaterial in the meniscus will therefore be able to promote tissue regeneration). Furthermore, providing directional cues, such as chemotactic gradients to guide cells like endogenous cells to the injury site. Recently, some studies have shown that allowing migration of cells provides a motivation for the cells to attach and drives the cellular colonisation process (Mauck & Burdick, 2015; Greiner et al., 2014);

5. The biomaterial should have biodegradable properties and be able to remodel as the novel cartilage grows, embeds and replaces the original construct; therefore, the matrix must be non-toxic, non-adhering and non-stimulating for inflammatory cells. The biomaterial for a meniscus should therefore facilitate host tissue integration and provide the appropriate biomechanical function in the knee.

6. Furthermore, they should be non-immunogenic as this is catastrophic for the biomaterial insertion. For any biomaterial, this is important, to prevent rejection the appropriate level of biocompatibility and non-toxic ability needs to be considered.

Biocompatibility

One of the most important non-mechanical requirements of orthopaedic biomaterials is biocompatibility. Biocompatibility is the ability of a substrate to exist in contact with tissues of the human body without causing an unacceptable degree of harm in the body. The biomaterial domain has been aptly described by Mardis and Kroeger, “the utopian state where a biomaterial presents an interface with physiologic environment without the material adversely affecting the environment or environment adversely affecting the biomaterial” (Mardis & Kroeger, 1988). An understanding of biocompatibility requires an appreciation of tissue cell, bacterial cell and host defence response to the insertion of a biomaterial in particular for this review—for meniscal interventions. Once the biomaterial has been placed into the body, a conditioning film containing biomolecules such as; water, electrolytes, cholesterol, vitamins, lipids and proteins (Chapman et al., 2013) (albumin, igG, fibronectin, fibrinogen, laminin, collagen and osteopontin) form on the surface long before cells are present and reach the state of equilibrium (Thevenot, Hu & Tang, 2008). In the very early implantation period or injury for this matter, inflammatory cells begin to proliferate, this is an immediate response (Anderson, Rodriguez & Chang, 2008). The first contact with tissue, proteins in blood and the interstitial fluids adsorb on to the biomaterial surface. An injury to vascularised connective tissue initiates the inflammatory response but also leads to the process of thrombus formation involving the activation of the extrinsic and also intrinsic coagulation, complement, fibrinolytic, kinin-generating systems and platelets (Anderson, Rodriguez & Chang, 2008). The conditioning layer represents a dynamic, ever-changing layer due to differential diffusion and mass transport of molecules in and out of the implant surface. Later stages of competitive binding then occur on the surface of the material owing to functional groups within the molecules. Cells therefore never see the ‘true’ surface of the biomaterial, but more correctly, respond and interact to a conditioned film that has consequently developed in-situ.

Following the conditioning sequence of the biomaterial, attachment cells secure themselves to the protein and protein matrices using integrin receptors. Thus, this conditioning layer is vital to the reaction of cells to the surface of the implanted biomaterial. The introduction of the biomaterial, the conditioning and immune response sequence is not always obvious as proteins have the ability to conform and expose epitopes that are not always identified as self-produced by the body’s immune system. Immune cells react as they detect what were once normal proteins and recognise them as foreign bodies. This process can result in a cascade of blood coagulation and chronic inflammation that can lead to occlusion of nutrients, changes in oxygen and fibrous capsule formation—operating toward total rejection by the body of the implanted biomaterial (Nasab & Hassan, 2010). The extent of the deformation process for proteins has been remedied based on the selection of material type. Surfaces are made more “passive” where chemical treatments are added to the manufacturing process. Passivation with acids such as nitric acid of stainless steel creates a less reactive oxide layer; this has been shown to improve the biocompatibility process. One added benefit to passivation is it serves as a means for removing foreign material from the surface, such as bacteria or biofilms (Blumenfeld & Bargar, 2006). Passivation can also be used to surface-modify natural or synthetic polymer biomaterial substrates for meniscal tear applications. For example, albumin, where the resulting surface passivation has been shown to reduce and prevent clotting (Kaur, 2017; Hanker & Giammara, 1988).

Role of biomaterials in meniscal repair

An article by Abrams et al. (2013) has shown that while there was no increase in the overall number of meniscal procedures, over a seven-year period there has been an 11.4% increase in isolated meniscal repairs and a 48.3% increase in meniscal repairs in combination with ACL reconstruction. This sharp increase in meniscal repair treatment is mainly due to the increased knowledge in the importance of the preservation of the meniscus to maintain normal knee function and prevent osteoarthritis. It has been shown that following meniscal repair, peak contact pressures are similar to that experienced with an intact meniscus (Bedi et al., 2010). Unfortunately, it is estimated that currently only 20% of all meniscal tears are repairable. Tears in the meniscal periphery (i.e., the red-red vascular zone) are most likely to heal whereas those in the meniscal avascular zone (i.e., the white-white zone) are unlikely to heal and those in the red-white zone have the potential to heal (Belzer & Cannon, 1993; Noyes & Barber-Westin, 2012). Besides vascularisation, tear type and various patient characteristics can influence decision making on treatment options and success of a meniscal repair. Typically, tears that are less than 2 cm in length, longitudinal and acute are more amendable to repair than larger tears (Taylor & Rodeo, 2013; Laible, Stein & Kiridly, 2013). Meniscal repairs are also not typically recommended for degenerative tears and thus repair success is typically superior in young patients (less than 50 years of age) (Laible, Stein & Kiridly, 2013). When appropriately performed, meniscal repairs provide considerable improvements in terms of clinical outcome and osteoarthritis prevention compared to a partial meniscectomy (Stein et al., 2010). Thus, finding ways to increase the number of meniscal tears that can be treated by meniscal reparation is of great importance.

Vascularisation in the meniscus tissue is of high relevance to biomaterial design. From prenatal development up until after birth, the meniscus is fully vascularised. Following this, from the age of ten, vascularisation reduces to 30% of the meniscus and at maturity the meniscus only in the peripheral region of approximately 10% of the tissue. Vascularisation represents another challenge in meeting the requirements of success for biomaterial implantation as a meniscus operation. Vascular endothelial growth factor enhances the blood vessel density in peri-implant spaces. Biomaterial scaffolds of knee menisci exist in a highly challenging environment as little vascular support is provided in this region of the body. Electrospinning of polymeric fibres can be produced to support other engineering applications such as blood vessel, tendons, meniscus and cartilage (Xu et al., 2004). Some authors have used unique biodegradable nanofibers as a scaffold to support blood vessel engineering. They have demonstrated that fibres of 500 nm with an aligned topography is able to mimic the circumferential orientation of cells and fibrils (Leong et al., 2009). The authors have postulated that macrophage within the CES produce angiogeneic growth factors that potentially stimulates vascularisation.

Role of biomaterials in meniscal replacement/regeneration

Owing to the limited percentage of meniscal tears that can be repaired and the poor clinical results with untreated symptomatic meniscal injuries and partial meniscectomy, biomaterial synthetic and allogeneic (genetically dissimilar) interacting biomaterials have been investigated to serve as a matrix to lead meniscal regeneration medicine, particularly as a cellular support.

Discovery of new biomaterials—beyond state of the art

The next phase in developing knee meniscal biomaterials for replacement and or regeneration applications extends to the design, discovery and evaluation of bioactive materials.

Bioactive meniscal materials have been used with some significantly exciting and promising results. For example, bioactive scaffolds have been shown to modulate local ECM density to improve repair (Shin, Jo & Mikos, 2003). A novel biphasic collagen scaffold and shown to support meniscal repair in vivo to support meniscal cell ingrowth but also producing ECM in vitro by Howard et al. (2016). The authors have shown that the addition of PRP enhanced scaffold enhanced healing (Howard et al., 2016). Other emerging materials which could show potential in meniscal repair include: cartilage matrix is also a promising material for cartilage regeneration given the emerging evidence supporting its chondroinductive character. The cartilage matrix is a promising material for hyaline cartilage tissue engineering applications and has been shown that cell derived matrix and ECM materials and have been demonstrated to show established decellularisation, representing an excellent and promising choice of new material for future direction. (Redman, Oldfield & Archer, 2005). A drawback so far is that the FDA regulatory approval may affect the decision to use a native or cell-derived matrix. To expedite FDA approval, a full chemical decellularisation of allogeneic matrix may be used—this way, removal of cells ensures no cross-species interactions (Sutherland et al., 2015). For example, allogeneic cells from bone marrow can be used in cardiac repair (Lemcke et al., 2017).

Initially, this is a relatively straightforward process whereby advanced synthesis of new materials can be performed. The difficulty lies with producing the novel activity and evaluation of the behaviour of the material in the biological system. Adapting the surface properties through the addition of synthetic peptides and or molecular drugs can yield thousands of candidate materials for testing. This approach has already been realised in the form of library derived screening techniques using commercially available methacrylate monomers—influencing attachment, growth, proliferation and differentiation of human embryonic stem cells (Anderson, Levenberg & Langer, 2004).

Further developments in biomaterials will continue to expand at the interface of nanotechnology. Understanding the tribological interaction with the surrounding interface of the human body is an approach that is being realised using the “bottom-up” approach (Zur et al., 2011). The bottom up approach will develop novel, self-assembling and environment reactive biomaterials. In particular, self-assembling peptides offer a new approach owing to the large variety of sequences that can be produced by chemical synthesis. These advances include the design of short peptides that have the ability to resemble nanofilaments which are compatible in vitro, without rejection. The use of peptides in polymeric materials allows for resistance in concentration, pH or level of divalent cation variability (Hartgerink, Beniash & Stupp, 2002).

The use of combinational gene therapy and biomaterial approaches is a recent technique to remedy meniscal lesions formed when orthopaedic surgery and loss of the meniscus has accelerated in the patient. The lack of therapeutic options suggests there is a need for improved treatments to enhance meniscal tear repair treatments/operations. Combinational approaches may also provide strategies to support this remedy (Cucchiarini et al., 2016). Gene therapy, can be directly applied as a combination or direct approach to meniscal repair strategies. A recent evaluation on gene therapy with cell and tissue engineering-based approaches demonstrates a six strategy approach: (a) directly using gene transfer vectors (Elsler et al., 2012), (b) administering genetically modified cells (Nakagawa et al., 2015), which could be fraught upon in some researching countries, continents, (c) implanting the biocompatible material that can deliver the recombinant factor, as we have seen rejection may be a potential problem with this result, (d) applying autologous platelet-rich plasma or fibrin clotting factors, (e) providing a biomaterial that delivers a gene transfer vector, (f) transplanting a material seeded with cells, again, we envisage a potential rejection with this treatment.