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Editorial Commentary: Biologic Augmentation of Meniscus Repair Is Complex

      Abstract

      In the setting of biological augmentation for meniscus repair, it is extremely important to evaluate all aspects, including effectiveness, costs, potential risks, benefits, and limitations. It seems that everything matters in healing: the aspirate source of the bioactive agents, cell content, presence of stem cells and their type, growth factors, cytokines, biomechanical scaffold, and the quality of the tissue. There are several differences among mesenchymal, adipose, and peripheral blood stem cells, with the cell origin affecting the differentiation potential towards bone, cartilage and ligament. Moreover, different aspirate sources and fibrin clots have different content in cells, growth factors, and cytokines. In this equation, it is not as simple as the more the better. Different doses of growth factors may have different effects in the different cell types. And as this was not complicated enough, synergistic phenomena between cells and between growth factors can play a huge role. Add to that the role of the biomechanical environment, the proper timing of the healing phases and the inherent patient characteristics. There is very, very much to learn, and finally, we acknowledge that not all menisci repairs can always heal.
      With recent advances in arthroscopic surgery, the task to “save the meniscus” is now possible not only for simple tears at the red–red vascular zone, but also in more complicated tears.
      • Lubowitz J.H.
      • Poehling G.G.
      Save the meniscus.
      The new challenge has become to attempt to successfully repair menisci tears even in the most difficult scenarios. Would it be possible to further enhance the biological and biomechanical environment of a repaired meniscus so it can successfully heal?
      In their article, “Biochemical Characteristics and Clinical Result of Bone Marrow–Derived Fibrin Clot For Repair of Isolated Meniscal Injury in the Avascular Zone,” Hashimoto, Nishino, Orita, Yamasaki, Nishida, Kinoshita, and Nakamura demonstrated a greater concentration in growth factors in bone marrow aspirate (BMA) fibrin clot compared with peripheral blood clot as well as with BMA and peripheral blood aspirates.
      • Hashimoto Y.
      • Nishino K.
      • Orita K.
      • et al.
      Biochemical characteristics and clinical result of bone marrow-derived fibrin clot for repair of isolated meniscal injury in the avascular zone.
      They also used BMA clots in meniscus repairs of horizontal, radial, and flap tear, with promising results.
      • Hashimoto Y.
      • Nishino K.
      • Orita K.
      • et al.
      Biochemical characteristics and clinical result of bone marrow-derived fibrin clot for repair of isolated meniscal injury in the avascular zone.
      When attempting to generalize these findings, careful evaluation of the meniscus tear characteristics and the patient population is important. For example, 23 of 30 tears were discoid meniscus tears, and patient mean age was 23.2 ± 9.6 years (range 13-46 years). This study provides early promising data supporting the use of BMA clot for meniscus tears. However, limitations, such as the lack of control group and the relatively low postoperative Tegner activity scale, highlight the need for additional and high level of evidence studies comparing the new biologic augmentation techniques.
      To advance outcomes in meniscus repair, 2 main strategic areas require further development. The first strategy is to improve the biomechanical quality of the repair at time zero and during the healing phase. On that front, several new ideas have recently shown promise using better tools, configurations, and materials to provide a stronger fixation and improved outcome.
      • Peterson J.
      • Paschos N.K.
      • Richmond J.C.
      Inside-out meniscal repair in the mid one-third of the menisci.
      • Zhang Z.-Z.
      • Luo H.
      • Zhang H.-Z.
      • et al.
      H-plasty repair technique improved tibiofemoral contact mechanics after repair for adjacent radial tears of posterior lateral meniscus root: A biomechanical study.
      • Saltzman B.M.
      • Habet N.A.
      • Rao A.J.
      • et al.
      Biomechanical evaluation of an all-inside posterior medial meniscal root repair technique via suture fixation to the posterior cruciate ligament.
      • Kurzweil P.
      • Krych A.J.
      • Anz A.
      • et al.
      Repair of horizontal cleavage meniscus tears. Results from a prospective multi-center STITCH trial.
      • Yoon K.H.
      • Park J.-Y.
      • Kwon Y.B.
      • Lee Y.J.
      • Kim E.J.
      • Kim S.-G.
      Inside-out repair of the meniscus in concomitant anterior cruciate ligament reconstruction: Absorbable versus nonabsorbable sutures.
      Adopting all these strategies has resulted in expanding the indications for meniscus repair with healing rates that continuously improve, even in types of meniscus tears that would be considered nonrepairable in the past.
      • Cristiani R.
      • Parling A.
      • Forssblad M.
      • Edman G.
      • Engström B.
      • Stålman A.
      Meniscus repair does not result in an inferior short-term outcome compared with meniscus resection: An analysis of 5,378 patients with primary anterior cruciate ligament reconstruction.
      ,
      • Yang B.W.
      • Liotta E.S.
      • Paschos N.
      Outcomes of meniscus repair in children and adolescents.
      Second, we ought to further enhance the biologic environment of healing, applying evolving knowledge for scaffolds, cells, and growth factors. Ongoing research will lead to exciting stories of regeneration, vascularization, and stem cells with potential for application in meniscus tears.
      • Chahla J.
      • Papalamprou A.
      • Chan V.
      • et al.
      Assessing the resident progenitor cell population and the vascularity of the adult human meniscus.
      • Toratani T.
      • Nakase J.
      • Numata H.
      • et al.
      Scaffold-free tissue-engineered allogenic adipose-derived stem cells promote meniscus healing.
      • Takata Y.
      • Nakase J.
      • Shimozaki K.
      • Asai K.
      • Tsuchiya H.
      Autologous adipose-derived stem cell sheet has meniscus regeneration-promoting effects in a rabbit model.
      However, it is extremely important to understand the complexity of the biology of meniscus healing. And this complexity may explain the unpredictability of clinical success in meniscus healing.
      It seems that everything matters in healing: the aspirate source of the bioactive agents, cell content, presence of stem cells and their type, growth factors, cytokines, biomechanical scaffold, and the quality of the tissue. There are several differences among mesenchymal, adipose, and peripheral blood stem cells, with the cell origin affecting the differentiation potential toward bone, cartilage, and ligament.
      • Takata Y.
      • Nakase J.
      • Shimozaki K.
      • Asai K.
      • Tsuchiya H.
      Autologous adipose-derived stem cell sheet has meniscus regeneration-promoting effects in a rabbit model.
      • Chen M.
      • Guo W.
      • Gao S.
      • et al.
      Biomechanical stimulus-based strategies for meniscus tissue engineering and regeneration.
      • Le H.
      • Xu W.
      • Zhuang X.
      • Chang F.
      • Wang Y.
      • Ding J.
      Mesenchymal stem cells for cartilage regeneration.
      • Kwon H.
      • Brown W.E.
      • Lee C.A.
      • et al.
      Surgical and tissue engineering strategies for articular cartilage and meniscus repair.
      • Jacob G.
      • Shimomura K.
      • Krych A.J.
      • Nakamura N.
      The meniscus tear: A review of stem cell therapies.
      Moreover, different aspirate sources and fibrin clots have different content in cells, growth factors, and cytokines.
      • Le H.
      • Xu W.
      • Zhuang X.
      • Chang F.
      • Wang Y.
      • Ding J.
      Mesenchymal stem cells for cartilage regeneration.
      ,
      • Jacob G.
      • Shimomura K.
      • Krych A.J.
      • Nakamura N.
      The meniscus tear: A review of stem cell therapies.
      ,
      • Shoji T.
      • Nakasa T.
      • Yoshizuka M.
      • et al.
      Comparison of fibrin clots derived from peripheral blood and bone marrow.
      In this equation, it is not as simple as the more the better. Different doses of growth factors may have different effects in the different cell types.
      • Pangborn C.A.
      • Athanasiou K.A.
      Growth factors and fibrochondrocytes in scaffolds.
      ,
      • Tarafder S.
      • Gulko J.
      • Kim D.
      • et al.
      Effect of dose and release rate of CTGF and TGFβ3 on avascular meniscus healing.
      And if this was not complicated enough, synergistic phenomena between cells and between growth factors can play a huge role.
      • Kwon H.
      • Brown W.E.
      • Lee C.A.
      • et al.
      Surgical and tissue engineering strategies for articular cartilage and meniscus repair.
      ,
      • Paschos N.K.
      • Brown W.E.
      • Eswaramoorthy R.
      • Hu J.C.
      • Athanasiou K.A.
      Advances in tissue engineering through stem cell-based co-culture.
      ,
      • Makris E.A.
      • MacBarb R.F.
      • Paschos N.K.
      • Hu J.C.
      • Athanasiou K.A.
      Combined use of chondroitinase-ABC, TGF-β1, and collagen crosslinking agent lysyl oxidase to engineer functional neotissues for fibrocartilage repair.
      Add to that the role of the biomechanical environment, the proper timing of the healing phases, and the inherent patient characteristics, this is a pretty hard problem to solve.
      In the setting of biological augmentation for meniscus repair, it is extremely important to evaluate all aspects, including effectiveness, costs, potential risks, benefits, and limitations. Additional research is needed to shed more light in this fascinating microworld. More importantly, we need to ensure that all these amazing tools are used with appropriate clinical indications and that we acknowledge that not all menisci repairs can always heal.

      Supplementary Data

      References

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