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Nonoperative and Operative Soft-Tissue and Cartilage Regeneration and Orthopaedic Biologics of the Knee: An Orthoregeneration Network (ON) Foundation Review

Open AccessPublished:June 24, 2021DOI:https://doi.org/10.1016/j.arthro.2021.04.002

      Abstract

      Orthoregeneration is defined as a solution for orthopedic conditions that harnesses the benefits of biology to improve healing, reduce pain, improve function, and optimally, provide an environment for tissue regeneration. Options include: drugs, surgical intervention, scaffolds, biologics as a product of cells, and physical and electro-magnetic stimuli. The goal of regenerative medicine is to enhance the healing of tissue after musculoskeletal injuries as both isolated treatment and adjunct to surgical management, using novel therapies to improve recovery and outcomes. Various orthopaedic biologics (orthobiologics) have been investigated for the treatment of pathology involving the knee, including symptomatic osteoarthritis and chondral injuries, as well as injuries to tendon, meniscus, and ligament, including the anterior cruciate ligament. Promising and established treatment modalities include hyaluronic acid (HA) in liquid or scaffold form; platelet-rich plasma (PRP); bone marrow aspirate (BMA) comprising mesenchymal stromal cells (MSCs), hematopoietic stem cells, endothelial progenitor cells, and growth factors; connective tissue progenitor cells (CTPs) including adipose-derived mesenchymal stem cells (AD-MSCs) and tendon-derived stem cells (TDSCs); matrix cell–based therapy including autologous chondrocytes or allograft; vitamin D; and fibrin clot. Future investigations should standardize solution preparations, because inconsistent results reported may be due to heterogeneity of HA, PRP, BMAC, or MSC preparations and regimens, which may inhibit meaningful comparison between studies to determine the true efficacy and safety for each treatment.
      The goal of regenerative medicine in orthopaedic surgery is to incorporate solutions aimed at enhancing musculoskeletal healing and or modify symptoms after injury or degeneration to reduce pain and improve function by modulating the biologic environment to promote tissue restoration.
      • Rodeo S.A.
      • Bedi A.
      2019-2020 NFL and NFL Physician Society Orthobiologics Consensus Statement.
      The use of these techniques seeks to improve symptoms either by augmenting the healing of tissues that possess relatively poor intrinsic healing capabilities, including cartilage, menisci, tendon, and ligament, or by inhibiting biochemical pathways that might be associated with symptom generation.
      • Rodeo S.A.
      • Bedi A.
      2019-2020 NFL and NFL Physician Society Orthobiologics Consensus Statement.
      Orthobiologic therapies are current used for the treatment of symptomatic focal chondral defects,
      • Magnussen R.A.
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      Treatment of focal articular cartilage defects in the knee: A systematic review.
      ,
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      Trends in the surgical treatment of articular cartilage lesions in the United States: an analysis of a large private-payer database over a period of 8 years.
      osteoarthritis (OA),
      • Filardo G.
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      • di Matteo B.
      • et al.
      Leukocyte-poor PRP application for the treatment of knee osteoarthritis.
      • Gobbi A.
      • Scotti C.
      • Karnatzikos G.
      • Mudhigere A.
      • Castro M.
      • Peretti G.M.
      One-step surgery with multipotent stem cells and hyaluronan-based scaffold for the treatment of full-thickness chondral defects of the knee in patients older than 45 years.
      • Gobbi A.
      • Whyte G.P.
      One-stage cartilage repair using a hyaluronic acid-based scaffold with activated bone marrow-derived mesenchymal stem cells compared with microfracture: Five-year follow-up.
      • Cole B.J.
      • Karas V.
      • Hussey K.
      • Pilz K.
      • Fortier L.A.
      Hyaluronic acid versus platelet-rich plasma: A prospective, double-blind randomized controlled trial comparing clinical outcomes and effects on intra-articular biology for the treatment of knee osteoarthritis.
      meniscal repair,
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      Bone marrow aspirate concentrate for the treatment of avascular meniscus tears in a one-step procedure-evaluation of an in vivo model.
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      Percutaneous injections of platelet rich plasma for treatment of intrasubstance meniscal lesions.
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      Arthroscopic inside-out repair of complete radial tears of the meniscus with a fibrin clot.
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      • Mills C.R.
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      Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy: A randomized, double-blind, controlled study.
      and tendon and ligament injuries.
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      Platelet-rich plasma as a treatment for patellar tendinopathy: A double-blind, randomized controlled trial.
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      The short-term effect after a single injection of high-molecular-weight hyaluronic acid in patients with enthesopathies (lateral epicondylitis, patellar tendinopathy, insertional Achilles tendinopathy, and plantar fasciitis): A preliminary study.
      Despite promising basic science data demonstrating the strong potential of multiple therapies, limited clinical data currently exist to support the use of these techniques.
      • Rodeo S.A.
      • Bedi A.
      2019-2020 NFL and NFL Physician Society Orthobiologics Consensus Statement.
      The potential utilization of orthobiologics to help restore function and accelerate recovery is of increasing interest to both patients and surgeons. Since 2017, the Orthoregeneration Network (ON) has served as an independent, international, nonprofit foundation driving development and understanding of new treatment options in the field of orthopaedic tissue regeneration. Orthoregeneration is defined as a solution for orthopedic conditions that harnesses the benefits of biology to improve healing, reduce pain, improve function, and optimally, provide an environment for tissue regeneration. Options include: drugs, surgical intervention, scaffolds, biologics as a product of cells, and physical and electro-magnetic stimuli.

      Orthoregeneration Network Glossary. https://my.on-foundation.org/Glossary. Accessed May 24, 2021.

      The mission of the ON is to provide guidance, education, and knowledge for surgeons to improve the use of tissue regeneration and biologic therapies in clinical practice. The purpose of this review is to summarize the current status of orthoregenerative therapies for orthopaedic issues related to the knee.

      Overview of Orthoregeneration in the Knee

      Cartilage possesses a poor inherent capacity for healing following injury. Partial-thickness cartilage lesions have no intrinsic reparative capacity, whereas a full-thickness defect that exposes bone will heal with biomechanically inferior fibrocartilage.
      • Sakata R.
      • Iwakura T.
      • Reddi A.H.
      Regeneration of articular cartilage surface: Morphogens, cells, and extracellular matrix scaffolds.
      ,
      • Chang Y.-H.
      • Liu H.-W.
      • Wu K.-C.
      • Ding D.-C.
      Mesenchymal stem cells and their clinical applications in osteoarthritis.
      As a result, orthobiologic treatments are aimed at the treatment of focal articular chondral defects
      • Southworth T.M.
      • Naveen N.B.
      • Nwachukwu B.U.
      • Cole B.J.
      • Frank R.M.
      Orthobiologics for focal articular cartilage defects.
      and generalized OA.
      • Filardo G.
      • Kon E.
      • di Matteo B.
      • et al.
      Leukocyte-poor PRP application for the treatment of knee osteoarthritis.
      • Gobbi A.
      • Scotti C.
      • Karnatzikos G.
      • Mudhigere A.
      • Castro M.
      • Peretti G.M.
      One-step surgery with multipotent stem cells and hyaluronan-based scaffold for the treatment of full-thickness chondral defects of the knee in patients older than 45 years.
      • Gobbi A.
      • Whyte G.P.
      One-stage cartilage repair using a hyaluronic acid-based scaffold with activated bone marrow-derived mesenchymal stem cells compared with microfracture: Five-year follow-up.
      • Cole B.J.
      • Karas V.
      • Hussey K.
      • Pilz K.
      • Fortier L.A.
      Hyaluronic acid versus platelet-rich plasma: A prospective, double-blind randomized controlled trial comparing clinical outcomes and effects on intra-articular biology for the treatment of knee osteoarthritis.
      ,
      • Vina E.R.
      • Kwoh C.K.
      Epidemiology of osteoarthritis: Literature update.
      • Brooks P.M.
      The burden of musculoskeletal disease—A global perspective.
      • Felson D.T.
      • Lawrence R.C.
      • Dieppe P.A.
      • et al.
      Osteoarthritis: New insights. Part 1: The disease and its risk factors.
      Similarly, the meniscus has poor intrinsic healing potential for lesions in the inner, avascular zone, leading to interest in the role of orthobiologics for the treatment of meniscal injuries, as well as to augment meniscal repair, owing to the challenges associated with meniscal healing.
      • Arnoczky S.P.
      • Warren R.F.
      Microvasculature of the human meniscus.
      ,
      • Taylor S.A.
      • Rodeo S.A.
      Augmentation techniques for isolated meniscal tears.
      Orthobiologics have also been reported as an alternative and an adjunct treatment for tendon and ligament pathology.
      • Chahla J.
      • Kennedy M.I.
      • Aman Z.S.
      • LaPrade R.F.
      Ortho-biologics for ligament repair and reconstruction.
      Hyaluronic acid (HA) is a high molecular weight glucosamine generated by native chondrocytes, providing viscoelasticity and lubrication within the knee joint.
      • Lin K.-Y.
      • Yang C.-C.
      • Hsu C.-J.
      • Yeh M.-L.
      • Renn J.-H.
      Intra-articular injection of platelet-rich plasma is superior to hyaluronic acid or saline solution in the treatment of mild to moderate knee osteoarthritis: A randomized, double-blind, triple-parallel, placebo-controlled clinical trial.
      In the arthritic knee, the concentration of HA has been reported to be decreased by 33% to 50% of normal levels.
      • Kon E.
      • Filardo G.
      • Drobnic M.
      • et al.
      Non-surgical management of early knee osteoarthritis.
      ,
      • Watterson J.R.
      • Esdaile J.M.
      Viscosupplementation: Therapeutic mechanisms and clinical potential in osteoarthritis of the knee.
      HA injections are believed to mechanistically improve symptoms through a variety of mechanisms in addition to stimulating the production of HA from chondrocytes and synoviocytes, providing lubrication properties to protect the cartilage against mechanical stresses and potentially protecting against further chondral damage.
      • Kon E.
      • Filardo G.
      • Drobnic M.
      • et al.
      Non-surgical management of early knee osteoarthritis.
      ,
      • Williams J.M.
      • Plaza V.
      • Hui F.
      • Wen C.
      • Kuettner K.E.
      • Homandberg G.A.
      Hyaluronic acid suppresses fibronectin fragment mediated cartilage chondrolysis: II. In vivo.
      Platelet-rich plasma (PRP) consists of harvested autologous blood concentrated through centrifugation to contain a minimum of 1.5- to 9-fold greater concentration of platelets compared with baseline serum levels.
      • Nguyen R.T.
      • Borg-Stein J.
      • McInnis K.
      Applications of platelet-rich plasma in musculoskeletal and sports medicine: An evidence-based approach.
      ,
      • Deal J.B.
      • Smith E.
      • Heard W.
      • O’Brien M.J.
      • Savoie 3rd, F.H.
      Platelet-rich plasma for primary treatment of partial ulnar collateral ligament tears: MRI correlation with results.
      PRP injections have been shown to stimulate platelet activation, leading to the release of various cytokines, growth factors, and inflammatory mediators and immune-modulating proteins, facilitating tissue healing by suppressing inflammation while promoting collagen synthesis, cell proliferation, and differentiation.
      • DeLong J.M.
      • Russell R.P.
      • Mazzocca A.D.
      Platelet-rich plasma: The PAW classification system.
      • Eppley B.L.
      • Woodell J.E.
      • Higgins J.
      Platelet quantification and growth factor analysis from platelet-rich plasma: Implications for wound healing.
      • Moatshe G.
      • Morris E.R.
      • Cinque M.E.
      • et al.
      Biological treatment of the knee with platelet-rich plasma or bone marrow aspirate concentrates.
      • van Buul G.M.
      • Koevoet W.L.M.
      • Kops N.
      • et al.
      Platelet-rich plasma releasate inhibits inflammatory processes in osteoarthritic chondrocytes.
      Bone marrow aspirate (BMA) as well as bone marrow aspirate concentrate (BMAC) effectively deliver mesenchymal stromal cells (MSCs), hematopoietic stem cells, endothelial progenitor cells, and various growth factors.
      • Yokoya S.
      • Mochizuki Y.
      • Natsu K.
      • Omae H.
      • Nagata Y.
      • Ochi M.
      Rotator cuff regeneration using a bioabsorbable material with bone marrow-derived mesenchymal stem cells in a rabbit model.
      BMAC has been shown to express strong regenerative properties for the treatment of chondral injuries, owing to the secretion of growth factor and cytokines from the surrounding tissues.
      • Chahla J.
      • Mandelbaum B.R.
      Biological treatment for osteoarthritis of the knee: Moving from bench to bedside—Current practical concepts.
      BMAC has been shown to increase chondrocyte proliferation and MSC differentiation, while aiding in wound healing and anti-inflammation by suppressing pro-inflammatory cytokines.
      • Cotter E.J.
      • Wang K.C.
      • Yanke A.B.
      • Chubinskaya S.
      Bone marrow aspirate concentrate for cartilage defects of the knee: From bench to bedside evidence.
      Many tissues contain a population of connective tissue progenitor cells (CTPs) that are characterized by the potential to undergo self-renewal, differentiating into various cell lines.
      • Sherman B.J.
      • Chahla J.
      • Glowney J.
      • Frank R.M.
      The role of orthobiologics in the management of osteoarthritis and focal cartilage defects.
      CTPs have also demonstrated immune-suppressive and anti-inflammatory properties, while producing proteins capable of cartilage regeneration.
      • Chang Y.-H.
      • Liu H.-W.
      • Wu K.-C.
      • Ding D.-C.
      Mesenchymal stem cells and their clinical applications in osteoarthritis.
      ,
      • Simmons P.J.
      • Torok-Storb B.
      Identification of stromal cell precursors in human bone marrow by a novel monoclonal antibody, STRO-1.
      • Dar A.
      • Goichberg P.
      • Shinder V.
      • et al.
      Chemokine receptor CXCR4-dependent internalization and resecretion of functional chemokine SDF-1 by bone marrow endothelial and stromal cells.
      • Dimarino A.M.
      • Caplan A.I.
      • Bonfield T.L.
      Mesenchymal stem cells in tissue repair.
      CTPs are commonly isolated from the bone marrow, adipose tissue, muscle tissue, synovial tissue, amniotic fluid, and placenta tissue.
      • Sherman B.J.
      • Chahla J.
      • Glowney J.
      • Frank R.M.
      The role of orthobiologics in the management of osteoarthritis and focal cartilage defects.
      Recently, adipose-derived stromal cells (AD-MSCs) have become increasingly popular because of ease of accessibility and harvest,
      • Ruetze M.
      • Richter W.
      Adipose-derived stromal cells for osteoarticular repair: Trophic function versus stem cell activity.
      ,
      • LaPrade R.F.
      • Geeslin A.G.
      • Murray I.R.
      • et al.
      Biologic treatments for sports injuries II think tank-current concepts, future research, and barriers to advancement, Part 1: Biologics overview, ligament injury, tendinopathy.
      as they possess ≤300-fold more stem cells per volume than BMAC.
      • Oedayrajsingh-Varma M.J.
      • van Ham S.M.
      • Knippenberg M.
      • et al.
      Adipose tissue-derived mesenchymal stem cell yield and growth characteristics are affected by the tissue-harvesting procedure.
      ,
      • Aust L.
      • Devlin B.
      • Foster S.J.
      • et al.
      Yield of human adipose-derived adult stem cells from liposuction aspirates.
      It is imperative to note that the benefits of these agents may have little to do with progenitor cell differentiation but rather are likely due to a paracrine influence in the environment into which they are placed.

      Pathology of the Articular Cartilage

      Focal defects to the articular cartilage within the knee are common, present in ≤60% of patients undergoing knee arthroscopy.
      • Southworth T.M.
      • Naveen N.B.
      • Nwachukwu B.U.
      • Cole B.J.
      • Frank R.M.
      Orthobiologics for focal articular cartilage defects.
      ,
      • Widuchowski W.
      • Widuchowski J.
      • Trzaska T.
      Articular cartilage defects: Study of 25,124 knee arthroscopies.
      Focal chondral lesions result in alterations in loading due to decreased contact area, placing greater stress on the surrounding cartilage, increasing the potential for degeneration and the development of early-onset OA.
      • Southworth T.M.
      • Naveen N.B.
      • Nwachukwu B.U.
      • Cole B.J.
      • Frank R.M.
      Orthobiologics for focal articular cartilage defects.
      ,
      • Prakash D.
      • Learmonth D.
      Natural progression of osteo-chondral defect in the femoral condyle.
      ,
      • Guettler J.H.
      • Demetropoulos C.K.
      • Yang K.H.
      • Jurist K.A.
      Osteochondral defects in the human knee: Influence of defect size on cartilage rim stress and load redistribution to surrounding cartilage.
      Early intervention for the treatment of focal chondral defects, with or without surgical intervention, is recommended to improve joint function, restore contact kinematics, and minimize the risk for further injury and arthritic development (Table 1).
      • Southworth T.M.
      • Naveen N.B.
      • Nwachukwu B.U.
      • Cole B.J.
      • Frank R.M.
      Orthobiologics for focal articular cartilage defects.
      Table 1Regenerative therapy for articular cartilage pathology—clinical studies summary
      StudyLOEYear of PublicationType of InterventionAdjunctive to Surgery (Y/N)Sample SizeIntervention DetailsFollow-Up (mo)Favorable Outcome (Y/N)Results Summary
      Test GroupControl GroupTest GroupControl Group
      Gobbi et al.
      • Gobbi A.
      • Whyte G.P.
      One-stage cartilage repair using a hyaluronic acid-based scaffold with activated bone marrow-derived mesenchymal stem cells compared with microfracture: Five-year follow-up.
      II2016HA scaffold + BMACN2750HA scaffold + BMACMfx60YAt 5 y, significantly better Tegner, IKDC objective, and KOOS scores in the HA scaffold + BMAC group
      Danieli et al
      • Danieli M.V.
      • Guerreiro J.P.F.
      • Queiroz A.O.
      • da Rosa Pereira H.
      • Cataneo D.C.
      Leucocyte-poor-platelet-rich plasma intra-operative injection in chondral knee injuries improve patients outcomes. A prospective randomized trial.
      II2020LP-PRPY3331LP-PRP + chondroplasty/debridementChondroplasty/debridement24YSignificant improvement in IKDC, KOOS, and Tegner scores in the PRP group
      Lee et al.
      • Lee G.W.
      • Son J.-H.
      • Kim J.-D.
      • Jung G.-H.
      Is platelet-rich plasma able to enhance the results of arthroscopic microfracture in early osteoarthritis and cartilage lesion over 40 years of age?.
      IV2013PRP + MfxY2425PRP + MfxMfx24YAt 2 y, significantly better VAS, IKDC scores, and tissue quality on postarthroscopic findings in the PRP + Mfx group
      Papali et al.
      • Papalia R.
      • Diaz Balzani L.
      • Torre G.
      • et al.
      Intraoperative application platelet rich fibrin, postoperative injections OF PRP or microfracture only for osteochondral lesions of the knee: A five-year retrospective evaluation.
      IV2016PRP + Mfx (intraop) PRP + MfxY3117PRP + Mfx (postop)Mfx60YSignificant improvement in IKDC, VAS pain, and improved postoperative appearance of cartilage on MRI in PRP + Mfx group
      Oladeji et al.
      • Oladeji L.O.
      • Stannard J.P.
      • Cook C.R.
      • et al.
      Effects of autogenous bone marrow aspirate concentrate on radiographic integration of femoral condylar osteochondral allografts.
      III2017BMA + OCA graftY2917BMA + OCA graftOCA graft alone6YSignificantly improved OCA graft incorporation at 6 mo with reduced sclerosis in BMA group
      Jo et al.
      • Jo C.H.
      • Chai J.W.
      • Jeong E.C.
      • et al.
      Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: A 2-year follow-up study.
      III2017ASCN126High-dose ASC (n = 12)Low-dose ASC (n = 3), medium-dose ASC (n = 3)24YAll groups had improvement in PROs with increase in cartilage and decrease in defect size at 6 mo; significant improvement in PROs with high-dose ASC
      Koh et al.
      • Koh Y.-G.
      • Kwon O.-R.
      • Kim Y.-S.
      • Choi Y.-J.
      • Tak D.-H.
      Adipose-derived mesenchymal stem cells with microfracture versus microfracture alone: 2-Year follow-up of a prospective randomized trial.
      I2016AD MSC4040AD MSCMFx27YClinical benefit for patients receiving adipose-derived MSC at 27 mo
      Hashimoto et al
      • Hashimoto Y.
      • Nishida Y.
      • Takahashi S.
      • et al.
      Transplantation of autologous bone marrow-derived mesenchymal stem cells under arthroscopic surgery with microfracture versus microfracture alone for articular cartilage lesions in the knee: A multicenter prospective randomized control clinical trial.
      II2019BM-MSCY74BM-MSC + MFxMFx alone12NNo clinical benefit for patients receiving BM-MSC + MFx at 48 wk
      Brittberg et al 2018
      • Brittberg M.
      • Recker D.
      • Ilgenfritz J.
      • Saris D.B.F.
      Matrix-applied characterized autologous cultured chondrocytes versus microfracture: Five-year follow-up of a prospective randomized trial.
      I2018MACIYMACIMFx60YClinical benefit for patients treated with ACI
      Fossum et al
      • Fossum V.
      • Hansen A.K.
      • Wilsgaard T.
      • Knutsen G.
      Collagen-covered autologous chondrocyte implantation versus autologous matrix-induced chondrogenesis: A randomized trial comparing 2 methods for repair of cartilage defects of the knee.
      I2019ACI-CY2120ACI-CAMIC24NNo difference between groups in KOOS at 24 mo
      Volz et al
      • Volz M.
      • Schaumburger J.
      • Frick H.
      • Grifka J.
      • Anders S.
      A randomized controlled trial demonstrating sustained benefit of autologous matrix-induced chondrogenesis over microfracture at five years.
      II2017AMICY309AMICMFx60YClinical improvement in modified Cincinnati score at 5 y with AMIC treatment
      Kon et al 2009
      • Kon E.
      • Gobbi A.
      • Filardo G.
      • Delcogliano M.
      • Zaffagnini S.
      • Marcacci M.
      Arthroscopic second-generation autologous chondrocyte implantation compared with microfracture for chondral lesions of the knee: Prospective nonrandomized study at 5 years.
      I2009ACI-CYACI-CMFx60YImproved IKDC and Tegner for patients receiving ACI at 5 y compared with MFx
      Niemeyer et al
      • Niemeyer P.
      • Laute V.
      • Zinser W.
      • et al.
      A prospective, randomized, open-label, multicenter, phase III noninferiority trial to compare the clinical efficacy of matrix-associated autologous chondrocyte implantation with spheroid technology versus arthroscopic microfracture for cartilage defects.
      II2019Scaffold-free ACIY5250Scaffold-free ACIMFx24NNo benefit in overall KOOS for patients receiving ACI
      ACI, autologous chondrocyte implantation; ACI-C; autologous chondrocyte implantation-collagen; AD, adipose-derived; AMIC, autologous matrix induced collagen; ASC, adipose stem cell; BM, bone marrow; BMA, bone marrow aspirate; BMAC, bone marrow aspirate concentrate; HA, hyaluronic acid; IKDC, International Knee Documentation Committee; KOOS, Knee Injury and Osteoarthritis Outcome Score; LOE, level of evidence; LP, leukocyte-poor; MACI, matrix induced chondrocyte implantation; Mfx, microfracture; MRI, magnetic resonance imaging; MSC, mesenchymal stromal cell; OCA, osteochondral allograft; PRO, patient-reported outcome; PRP, platelet-rich plasma; VAS, visual analog score.

      Hyaluronic Acid

      The role of HA for the treatment of focal chondral defects has primarily been described in combination with surgical procedures.
      • Gobbi A.
      • Scotti C.
      • Karnatzikos G.
      • Mudhigere A.
      • Castro M.
      • Peretti G.M.
      One-step surgery with multipotent stem cells and hyaluronan-based scaffold for the treatment of full-thickness chondral defects of the knee in patients older than 45 years.
      ,
      • Sherman B.J.
      • Chahla J.
      • Glowney J.
      • Frank R.M.
      The role of orthobiologics in the management of osteoarthritis and focal cartilage defects.
      ,
      • Sadlik B.
      • Gobbi A.
      • Puszkarz M.
      • Klon W.
      • Whyte G.P.
      Biologic inlay osteochondral reconstruction: Arthroscopic one-step osteochondral lesion repair in the knee using morselized bone grafting and hyaluronic acid-based scaffold embedded with bone marrow aspirate concentrate.
      The combination of an HA scaffold + BMAC injection with arthroscopic debridement for focal cartilage lesions without microfracture has been shown to yield superior clinical outcomes at 5-year follow-up compared with isolated microfracture.
      • Gobbi A.
      • Whyte G.P.
      One-stage cartilage repair using a hyaluronic acid-based scaffold with activated bone marrow-derived mesenchymal stem cells compared with microfracture: Five-year follow-up.
      Hyaline-like cartilage has been reported to develop within defects, resulting in improved pain and functional outcome scores when HA is used with BMAC + osteochondral grafting in patients with high-grade cartilage lesions.
      • Gobbi A.
      • Scotti C.
      • Karnatzikos G.
      • Mudhigere A.
      • Castro M.
      • Peretti G.M.
      One-step surgery with multipotent stem cells and hyaluronan-based scaffold for the treatment of full-thickness chondral defects of the knee in patients older than 45 years.
      ,
      • Sadlik B.
      • Gobbi A.
      • Puszkarz M.
      • Klon W.
      • Whyte G.P.
      Biologic inlay osteochondral reconstruction: Arthroscopic one-step osteochondral lesion repair in the knee using morselized bone grafting and hyaluronic acid-based scaffold embedded with bone marrow aspirate concentrate.

      Platelet-Rich Plasma

      Isolated use of PRP for focal chondral defects has been infrequently reported. When used as an adjunct during surgery, PRP has demonstrated promising results. In patients with International Cartilage Repair Society (ICRS) grade III knee chondral injuries treated by chondroplasty and PRP, Danieli et al.
      • Danieli M.V.
      • Guerreiro J.P.F.
      • Queiroz A.O.
      • da Rosa Pereira H.
      • Cataneo D.C.
      Leucocyte-poor-platelet-rich plasma intra-operative injection in chondral knee injuries improve patients outcomes. A prospective randomized trial.
      reported significant improvements in outcomes out to 2 years compared with chondroplasty alone. Lee et al.
      • Lee G.W.
      • Son J.-H.
      • Kim J.-D.
      • Jung G.-H.
      Is platelet-rich plasma able to enhance the results of arthroscopic microfracture in early osteoarthritis and cartilage lesion over 40 years of age?.
      reported improved clinical outcomes and tissue quality for patients undergoing microfracture + PRP injection versus microfracture alone for focal chondral lesions <4 cm2 with minimum 2-year follow-up. Papalia et al.
      • Papalia R.
      • Diaz Balzani L.
      • Torre G.
      • et al.
      Intraoperative application platelet rich fibrin, postoperative injections OF PRP or microfracture only for osteochondral lesions of the knee: A five-year retrospective evaluation.
      reported that patients treated with microfracture + PRP injected either intraoperatively or postoperatively reported greater improvement in clinical outcome scores and magnetic resonance imaging (MRI) appearance of cartilage compared with microfracture alone.

      Bone Marrow Aspirate Concentrate

      Injection of BMAC + HA scaffold with concurrent arthroscopic debridement has been reported to result in superior results at 5-year follow-up compared with microfracture alone for cartilage lesions measuring 0.5 to 2.2 cm.
      • Gobbi A.
      • Whyte G.P.
      One-stage cartilage repair using a hyaluronic acid-based scaffold with activated bone marrow-derived mesenchymal stem cells compared with microfracture: Five-year follow-up.
      Improved cartilage maturation and fill has been reported in patients with grade 3 or 4 chondral defects undergoing treatment with a scaffold supplemented with BMAC compared with patients treated with scaffold alone.
      • van Buul G.M.
      • Koevoet W.L.M.
      • Kops N.
      • et al.
      Platelet-rich plasma releasate inhibits inflammatory processes in osteoarthritic chondrocytes.
      When evaluating the efficacy of BMAC in an HA scaffold compared with microfracture alone for full-thickness chondral defects, Whyte et al.
      • Whyte G.P.
      • Gobbi A.
      • Sadlik B.
      Dry arthroscopic single-stage cartilage repair of the knee using a hyaluronic acid-based scaffold with activated bone marrow-derived mesenchymal stem cells.
      reported significant improvement in clinical outcomes in 50 patients at 2-year follow-up. Moreover, 100% of patients classified their functionality as “normal” or “nearly normal” compared with only 64% of patients undergoing microfracture. A follow-up study reported maintained improvements in clinical outcomes and functionality at 5-year follow up.
      • Gobbi A.
      • Whyte G.P.
      One-stage cartilage repair using a hyaluronic acid-based scaffold with activated bone marrow-derived mesenchymal stem cells compared with microfracture: Five-year follow-up.
      Oladeji et al.
      • Oladeji L.O.
      • Stannard J.P.
      • Cook C.R.
      • et al.
      Effects of autogenous bone marrow aspirate concentrate on radiographic integration of femoral condylar osteochondral allografts.
      examined outcomes for osteochondral grafts saturated in BMAC for 2 minutes before transplantation compared with grafts without BMAC. Graft incorporation was found to be significantly increased in the BMAC group at 6 months, with significantly less sclerosis appreciated at 6-week and 3-month follow-ups.

      Mesenchymal Stromal Cells

      A randomized controlled trial (RCT) found that isolated intraarticular injection of AD-MSCs for focal defects led to a significant improvement in clinical outcomes at 6-month follow-up, while significantly decreasing defect size and increasing the amount of cartilage in the joint.
      • Jo C.H.
      • Chai J.W.
      • Jeong E.C.
      • et al.
      Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: A 2-year follow-up study.
      When it was used as an adjunct during surgical intervention, Koh et al.
      • Koh Y.-G.
      • Kwon O.-R.
      • Kim Y.-S.
      • Choi Y.-J.
      • Tak D.-H.
      Adipose-derived mesenchymal stem cells with microfracture versus microfracture alone: 2-Year follow-up of a prospective randomized trial.
      found that in 80 patients with focal defects ≥3 cm2 treated with microfracture + AD-MSCs injection had improved MRI appearance of cartilage lesions at 2-year follow-up compared with patients undergoing microfracture alone. However, no difference in outcome scores or tissue quality during second-look arthroscopy were appreciated between groups. In contrast, an RCT comparing bone marrow–derived mesenchymal stem cells (BMSCs) with microfracture to microfracture alone reported no clinical benefit in patients receiving BMSCs with microfracture at 48 weeks.
      • Hashimoto Y.
      • Nishida Y.
      • Takahashi S.
      • et al.
      Transplantation of autologous bone marrow-derived mesenchymal stem cells under arthroscopic surgery with microfracture versus microfracture alone for articular cartilage lesions in the knee: A multicenter prospective randomized control clinical trial.

      Matrix Cell–Based Therapy

      The use of matrix cell–based cell therapy was reported by Brittberg et al.
      • Brittberg M.
      • Recker D.
      • Ilgenfritz J.
      • Saris D.B.F.
      Matrix-applied characterized autologous cultured chondrocytes versus microfracture: Five-year follow-up of a prospective randomized trial.
      to result in superior outcomes at 5-year follow-up compared with patients undergoing microfracture alone for symptomatic cartilage knee defects ≥3 cm2. Moreover, Fossum et al.
      • Fossum V.
      • Hansen A.K.
      • Wilsgaard T.
      • Knutsen G.
      Collagen-covered autologous chondrocyte implantation versus autologous matrix-induced chondrogenesis: A randomized trial comparing 2 methods for repair of cartilage defects of the knee.
      reported significant improvements in clinical outcomes at 2 years in patients with symptomatic chondral or osteochondral defects (>2 cm2) of the distal femur or patella treated with autologous matrix-induced chondrogenesis (AMIC®) or collagen-covered autologous chondrocyte implantation (ACI-C). Volz et al.
      • Volz M.
      • Schaumburger J.
      • Frick H.
      • Grifka J.
      • Anders S.
      A randomized controlled trial demonstrating sustained benefit of autologous matrix-induced chondrogenesis over microfracture at five years.
      reported significant functional improvement at ≤5 years in patients with isolated cartilage defects (2 to 3 cm2) of the knee located on the medial or lateral femoral condyle, trochlea, or patella treated with AMIC using a type I/III collagen membrane compared with microfracture alone. In addition, Kon et al.
      • Kon E.
      • Gobbi A.
      • Filardo G.
      • Delcogliano M.
      • Zaffagnini S.
      • Marcacci M.
      Arthroscopic second-generation autologous chondrocyte implantation compared with microfracture for chondral lesions of the knee: Prospective nonrandomized study at 5 years.
      reported that patients undergoing ACI-C for grade III to IV chondral lesions (1 to 5 cm2) of the femoral condyles or trochlea reported improved International Knee Documentation Committee (IKDC) and Tegner scores at 5 years compared with patients treated with microfracture alone. Meanwhile, treatment for chondral defects (1 to 4 cm2) with ACI using spheroids consisting of chondrocytes and their own extracellular matrix in a physiological sodium-chloride solution was reported by Niemeyer et al.
      • Niemeyer P.
      • Laute V.
      • Zinser W.
      • et al.
      A prospective, randomized, open-label, multicenter, phase III noninferiority trial to compare the clinical efficacy of matrix-associated autologous chondrocyte implantation with spheroid technology versus arthroscopic microfracture for cartilage defects.
      to result in improved functional outcomes and morphological repair in patients at ≤24 months.

      Pathology of Osteoarthritis

      Brief Overview

      Knee OA is the most common joint disorder in the United States.
      • Vina E.R.
      • Kwoh C.K.
      Epidemiology of osteoarthritis: Literature update.
      • Brooks P.M.
      The burden of musculoskeletal disease—A global perspective.
      • Felson D.T.
      • Lawrence R.C.
      • Dieppe P.A.
      • et al.
      Osteoarthritis: New insights. Part 1: The disease and its risk factors.
      Globally, knee OA was ranked as the 11th highest contributor to global disability.
      • Cross M.
      • Smith E.
      • Hoy D.
      • et al.
      The global burden of hip and knee osteoarthritis: Estimates from the global burden of disease 2010 study.
      As a progressive disease involving multiple metabolic, genetic, and biomechanical variables, no curative therapies currently exist for the treatment of knee OA.
      • Chahla J.
      • Mandelbaum B.R.
      Biological treatment for osteoarthritis of the knee: Moving from bench to bedside—Current practical concepts.
      ,
      • Haseeb A.
      • Haqqi T.M.
      Immunopathogenesis of osteoarthritis.
      ,
      • Lane N.E.
      • Brandt K.
      • Hawker G.
      • et al.
      OARSI-FDA initiative: Defining the disease state of osteoarthritis.
      The use of various orthobiologics alone and as an adjunct during surgical treatment for knee OA has gained increasing popularity to help improve function and decrease pain in patients with symptomatic knee OA (Table 2).
      Table 2Regenerative therapy for osteoarthritis—clinical studies summary
      StudyLOEYear of PublicationType of InterventionAdjunctive to Surgery (Y/N)Sample SizeIntervention DetailsFollow-Up (mo)Favorable Outcome (Y/N)Results Summary
      Test GroupControl GroupTest GroupControl Group
      Smith et al
      • Smith P.A.
      Intra-articular autologous conditioned plasma injections provide safe and efficacious treatment for knee osteoarthritis: An FDA-sanctioned, randomized, double-blind, placebo-controlled clinical trial.
      I2016LP-PRPN1515PRPCSI12YSignificant improvement of 78% in total WOMAC at 12 mo with single injection of PRP
      Forogh et al.
      • Forogh B.
      • Mianehsaz E.
      • Shoaee S.
      • Ahadi T.
      • Raissi G.R.
      • Sajadi S.
      Effect of single injection of platelet-rich plasma in comparison with corticosteroid on knee osteoarthritis: A double-blind randomized clinical trial.
      I2015PRPN2424PRP (single injection)CSI (single injection)6YSignificantly greater pain relief, ability to perform activities of daily living, and quality of life with single injection of PRP
      Lin et al.
      • Lin K.-Y.
      • Yang C.-C.
      • Hsu C.-J.
      • Yeh M.-L.
      • Renn J.-H.
      Intra-articular injection of platelet-rich plasma is superior to hyaluronic acid or saline solution in the treatment of mild to moderate knee osteoarthritis: A randomized, double-blind, triple-parallel, placebo-controlled clinical trial.
      I2019LP-PRPN6027LP-PRP (31); HA (29)NS (27)12YSignificantly greater and maintained improvement in WOMAC and IKDC scores with LP-PRP injection
      Cole et al.
      • Cole B.J.
      • Karas V.
      • Hussey K.
      • Pilz K.
      • Fortier L.A.
      Hyaluronic acid versus platelet-rich plasma: A prospective, double-blind randomized controlled trial comparing clinical outcomes and effects on intra-articular biology for the treatment of knee osteoarthritis.
      I2016LP-PRPN4950LP-PRPHA12YSignificant improvement in VAS and IKDC scores at 24- and 52-wk follow-up with LP-PRP
      Filardo et al.
      • Filardo G.
      • di Matteo B.
      • di Martino A.
      • et al.
      Platelet-rich plasma intra-articular knee injections show no superiority versus viscosupplementation: A randomized controlled trial.
      I2015LP-PRPN9489LP-PRPHA12NNo significant difference between 3 weekly injections of LR-PRP and single HA injections despite significant improvements in PROs
      di Martino et al.
      • di Martino A.
      • di Matteo B.
      • Papio T.
      • et al.
      Platelet-rich plasma versus hyaluronic acid injections for the treatment of knee osteoarthritis: Results at 5 years of a double-blind, randomized controlled trial.
      I2019LP-PRPN8582LP-PRPHA60NNo significant differences in outcomes between LR-PRP and HA at any time point
      Huang et al.
      • Huang Y.
      • Liu X.
      • Xu X.
      • Liu J.
      Intra-articular injections of platelet-rich plasma, hyaluronic acid or corticosteroids for knee osteoarthritis: A prospective randomized controlled study.
      I2019LP-PRPN8040LP-PRP (40); HA (40)CSI (40)12NSingle injection LP-PRP led to significantly lower WOMAC scores at 6, 9, and 12 mo compared with HA + CSI
      Shapiro et al.
      • Shapiro S.A.
      • Arthurs J.R.
      • Heckman M.G.
      • et al.
      Quantitative T2 MRI mapping and 12-month follow-up in a randomized, blinded, placebo controlled trial of bone marrow aspiration and concentration for osteoarthritis of the knees.
      I2018BMACN2525BMACSaline12NNo significant differences in ICOAP and VAS scores at 12 mo between BMAC and saline injection
      Lamo-Espinoza et al
      • Lamo-Espinosa J.M.
      • Mora G.
      • Blanco J.F.
      • et al.
      Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: Multicenter randomized controlled clinical trial (phase I/II).
      I2016BM MSC + HAN2010BM MSC + HAHA12YSignificant improvement in VAS and WOMAC at 6-and 12-mo follow-up with injection of AMSCs
      Emadedin et al
      • Emadedin M.
      • Labibzadeh N.
      • Liastani M.G.
      • et al.
      Intra-articular implantation of autologous bone marrow-derived mesenchymal stromal cells to treat knee osteoarthritis: A randomized, triple-blind, placebo-controlled phase 1/2 clinical trial.
      I2018BM MSC + HAN2225BM MSC + HAHA6ySignificant improvement in painless walking distance and WOMAC in patients receiving BM MSC, no significant difference in VAS
      Lu et al.
      • Lu L.
      • Dai C.
      • Zhang Z.
      • et al.
      Treatment of knee osteoarthritis with intra-articular injection of autologous adipose-derived mesenchymal progenitor cells: A prospective, randomized, double-blind, active-controlled, phase IIb clinical trial.
      I2019AMSCN2626BMACHA12YSignificant improvement in VAS and SF-12 at 6-and 12-mo follow-up with injection of AMSCs
      Lee et al.
      • Lee W.-S.
      • Kim H.J.
      • Kim K.-I.
      • Kim G.B.
      • Jin W.
      Intra-articular injection of autologous adipose tissue-derived mesenchymal stem cells for the treatment of knee osteoarthritis: A phase IIb, randomized, placebo-controlled clinical trial.
      I2019ASCN1212ASCSaline6NSignificant improvement in WOMAC score at 6-mo follow-up with both ASC and saline injection; no significant difference between groups
      Freitag et al.
      • Freitag J.
      • Bates D.
      • Wickham J.
      • et al.
      Adipose-derived mesenchymal stem cell therapy in the treatment of knee osteoarthritis: A randomized controlled trial.
      I2018ASCN2010ASC × 1 injection (10); ASC × 2 injections 10)No injections (10)12YSignificant improvements in VAS and WOMAC score in patients receiving BM MSC at 6 and 12 mo
      AMSC, adipose mesenchymal stem cell; ASC, adipose stem cell; BM, bone marrow; BMAC, bone marrow aspirate concentrate; CSI, corticosteroids; HA, hyaluronic acid; ICOAP, International Intermittent and Constant Osteoarthritis Pain; IKDC, International Knee Documentation Committee; LOE, level of evidence; LP, leukocyte-poor; MSC, mesenchymal stromal cell; NS, normal saline; PRO, patient-reported outcome; PRP, platelet-rich plasma; SF-12, 12-Item Short Form Health Survey; VAS, visual analog score; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

      Hyaluronic Acid

      The use of HA injections for the treatment of knee OA remains controversial despite its continued use for patients with moderate OA.
      • Carlson V.R.
      • Ong A.C.
      • Orozco F.R.
      • Hernandez V.H.
      • Lutz R.W.
      • Post Z.D.
      Compliance with the AAOS Guidelines for Treatment of Osteoarthritis of the Knee: A survey of the American Association of Hip and Knee Surgeons.
      The American Academy of Orthopaedic Surgeons reported in their 2013 clinical practice guidelines that HA use for the management of OA was not supported.
      • Jevsevar D.S.
      • Brown G.A.
      • Jones D.L.
      • et al.
      The American Academy of Orthopaedic Surgeons evidence-based guideline on: Treatment of osteoarthritis of the knee, 2nd edition.
      A meta-analysis analyzing 89 randomized trials involving 12,667 patients comparing HA to sham injections versus no intervention found that HA produced a small and clinically irrelevant benefit, leading the authors to discourage HA.
      • Campbell K.A.
      • Erickson B.J.
      • Saltzman B.M.
      • et al.
      Is local viscosupplementation injection clinically superior to other therapies in the treatment of osteoarthritis of the knee: A systematic review of overlapping meta-analyses.
      Meanwhile, a systematic review
      • Rutjes A.W.S.
      • Jüni P.
      • da Costa B.R.
      • Trelle S.
      • Nüesch E.
      • Reichenbach S.
      Viscosupplementation for osteoarthritis of the knee: A systematic review and meta-analysis.
      found that compared with nonsteroidal anti-inflammatory drugs, corticosteroids (CSI), PRP, and placebo, HA possessed the highest level of evidence supporting its use for early OA, with improvements in function and pain for ≤26 weeks. Moreover, the Osteoarthritis Research Society International group concluded that HA was preferable to CSI because of its beneficial effects on pain at and beyond 12 weeks.
      • Bannuru R.R.
      • Osani M.C.
      • Vaysbrot E.E.
      • et al.
      OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis.

      Platelet-Rich Plasma

      Outcomes following the use of PRP for the treatment of knee OA remain varied and controversial.
      • Smith P.A.
      Intra-articular autologous conditioned plasma injections provide safe and efficacious treatment for knee osteoarthritis: An FDA-sanctioned, randomized, double-blind, placebo-controlled clinical trial.
      An RCT reported that 3 weekly injections of PRP resulted in significant improvement in total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) of 78% at 12 months versus only a 7% improvement with saline injections.
      • Smith P.A.
      Intra-articular autologous conditioned plasma injections provide safe and efficacious treatment for knee osteoarthritis: An FDA-sanctioned, randomized, double-blind, placebo-controlled clinical trial.
      An RCT comparing 41 patients with moderate knee OA treated with a single PRP injection reported significantly greater pain relief, ability to perform activities of daily living, and quality of life versus CSI.
      • Forogh B.
      • Mianehsaz E.
      • Shoaee S.
      • Ahadi T.
      • Raissi G.R.
      • Sajadi S.
      Effect of single injection of platelet-rich plasma in comparison with corticosteroid on knee osteoarthritis: A double-blind randomized clinical trial.
      An RCT of 87 knees randomized to receive leukocyte-poor (LP)-PRP, normal saline, or HA reported that only the LP-PRP group maintained improvement in WOMAC and IKDC scores at 12-month follow-up.
      • Lin K.-Y.
      • Yang C.-C.
      • Hsu C.-J.
      • Yeh M.-L.
      • Renn J.-H.
      Intra-articular injection of platelet-rich plasma is superior to hyaluronic acid or saline solution in the treatment of mild to moderate knee osteoarthritis: A randomized, double-blind, triple-parallel, placebo-controlled clinical trial.
      Moreover, patients treated with LP-PRP were the only group to surpass the minimum clinically important difference in WOMAC scores. Meanwhile, Cole et al.
      • Cole B.J.
      • Karas V.
      • Hussey K.
      • Pilz K.
      • Fortier L.A.
      Hyaluronic acid versus platelet-rich plasma: A prospective, double-blind randomized controlled trial comparing clinical outcomes and effects on intra-articular biology for the treatment of knee osteoarthritis.
      analyzed 99 patients randomized to 3 weekly injections of LP-PRP versus HA and reported significant improvement in visual analog score (VAS) and IKDC scores at 24- and 52-week follow-up in the LP-PRP group.
      In contrast, a clinical trial of 192 patients with Kellgren-Lawrence (KL) knee OA grade <3 randomized to receive either 3 weekly injections of leukocyte-rich (LR)-PRP or HA injections reported that despite significant improvements in patient-reported outcomes (PROs) in both groups, no significant differences were noted between groups.
      • Filardo G.
      • di Matteo B.
      • di Martino A.
      • et al.
      Platelet-rich plasma intra-articular knee injections show no superiority versus viscosupplementation: A randomized controlled trial.
      di Martino et al.
      • di Martino A.
      • di Matteo B.
      • Papio T.
      • et al.
      Platelet-rich plasma versus hyaluronic acid injections for the treatment of knee osteoarthritis: Results at 5 years of a double-blind, randomized controlled trial.
      found in their RCT evaluating 5-year outcomes in 192 patients receiving either LR-PRP or HA injection that no significant differences in outcomes were observed at any time point between groups. When examining outcomes following LP-PRP injection versus CSI + HA in 120 patients, Huang et al.
      • Huang Y.
      • Liu X.
      • Xu X.
      • Liu J.
      Intra-articular injections of platelet-rich plasma, hyaluronic acid or corticosteroids for knee osteoarthritis: A prospective randomized controlled study.
      reported no significant differences at 3-month follow-up. Moreover, the LP-PRP group had significantly lower WOMAC scores at 6, 9, and 12 months after injection, with significantly lower VAS scores at 12 months.

      Bone Marrow Aspirate Concentrate

      Limited clinical data have been reported evaluating the efficacy of BMAC for the treatment of knee OA. Chahla et al.
      • Chahla J.
      • Cinque M.E.
      • Piuzzi N.S.
      • et al.
      A call for standardization in platelet-rich plasma preparation protocols and composition reporting: A systematic review of the clinical orthopaedic literature.
      reported in their systematic review that despite a number of studies reporting good to excellent outcomes with improvements in pain and function and few adverse side effects, no RCTs were included, with substantial heterogeneity existing between studies.
      • Shapiro S.A.
      • Kazmerchak S.E.
      • Heckman M.G.
      • Zubair A.C.
      • O’Connor M.I.
      A prospective, single-blind, placebo-controlled trial of bone marrow aspirate concentrate for knee osteoarthritis.
      ,
      • Kim J.-D.
      • Lee G.W.
      • Jung G.H.
      • et al.
      Clinical outcome of autologous bone marrow aspirates concentrate (BMAC) injection in degenerative arthritis of the knee.
      Recently, an RCT evaluating the efficacy of BMAC in 25 patients with bilateral knee OA (KL grade 1 to 3), with each joint randomized to receive either BMAC or saline injection, reported significant improvements in International Intermittent and Constant Osteoarthritis Pain (ICOAP) and VAS scores at 1-week and 3- and 6-month follow-up for both groups,
      • Shapiro S.A.
      • Kazmerchak S.E.
      • Heckman M.G.
      • Zubair A.C.
      • O’Connor M.I.
      A prospective, single-blind, placebo-controlled trial of bone marrow aspirate concentrate for knee osteoarthritis.
      with no significant difference noted between groups at any time point. A follow-up study at 12 months found significant improvements in pain for both groups, with no significant differences in outcomes between groups.
      • Shapiro S.A.
      • Arthurs J.R.
      • Heckman M.G.
      • et al.
      Quantitative T2 MRI mapping and 12-month follow-up in a randomized, blinded, placebo controlled trial of bone marrow aspiration and concentration for osteoarthritis of the knees.

      Mesenchymal Stromal Cells

      In an RCT of 30 patents with knee OA (KL grade 2 to 4), Lamo-Espinosa et al.
      • Lamo-Espinosa J.M.
      • Mora G.
      • Blanco J.F.
      • et al.
      Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: Multicenter randomized controlled clinical trial (phase I/II).
      reported that patients receiving injection of high-dose bone marrow–derived mesenchymal stromal cells (BM-MSCs) and HA had significant improvement in VAS and WOMAC at 6- and 12-month follow-up compared with patients treated with HA alone. Similarly Emadedin et al.
      • Emadedin M.
      • Labibzadeh N.
      • Liastani M.G.
      • et al.
      Intra-articular implantation of autologous bone marrow-derived mesenchymal stromal cells to treat knee osteoarthritis: A randomized, triple-blind, placebo-controlled phase 1/2 clinical trial.
      reported that patients with knee OA (KL grade 2 to 4) treated with intra-articular implantation of BM-MSCs had significant improvement in painless walking distance and WOMAC scores compared with placebo injection at 6-month follow-up.
      Lu et al.
      • Lu L.
      • Dai C.
      • Zhang Z.
      • et al.
      Treatment of knee osteoarthritis with intra-articular injection of autologous adipose-derived mesenchymal progenitor cells: A prospective, randomized, double-blind, active-controlled, phase IIb clinical trial.
      compared intra-articular injections of adipose-derived mesenchymal stem cells (AMSCs) digested in 0.075% type I collagenase solution, isolated via centrifugation and subsequently culture expanded via 3 passages, to HA in 53 patients with knee OA (KL grade 1 to 3) randomized to 1 of the 2 study arms. Patients undergoing AMSC injections reported significant improvement in VAS and 12-Item Short Form Health Survey (SF-12) at 6- and 12-month follow-up. A significant increase in the volume change of cartilage based on MRI was noted in the ASC group at 12-month follow-up. Clinical outcomes in 24 patients undergoing ASC versus saline injections reported a 55% improvement in WOMAC score at 6-month follow-up compared with baseline values (P < .001); however, no significant differences in improvement were observed between groups.
      • Lee W.-S.
      • Kim H.J.
      • Kim K.-I.
      • Kim G.B.
      • Jin W.
      Intra-articular injection of autologous adipose tissue-derived mesenchymal stem cells for the treatment of knee osteoarthritis: A phase IIb, randomized, placebo-controlled clinical trial.
      When examining the number of ASC injections, Freitag et al.
      • Freitag J.
      • Bates D.
      • Wickham J.
      • et al.
      Adipose-derived mesenchymal stem cell therapy in the treatment of knee osteoarthritis: A randomized controlled trial.
      analyzed 30 patients with knee OA (KL grade 2 to 3) randomized to receive 1 or 2 injections (at baseline and at 6 months) versus a control group treated without injection. Patients receiving 1 or 2 ASC injections had significant improvements in pain and WOMAC score compared with control patients at 12-month follow-up. Moreover, the minimum clinically important difference threshold was surpassed in 84.1% and 87.1% of the 1- and 2-injection groups, respectively. A systematic review of 16 studies analyzing the use of AD-MSCs for the treatment of knee OA reported improvements in clinical outcomes compared with baseline measures.
      • Hurley E.T.
      • Yasui Y.
      • Gianakos A.L.
      • et al.
      Limited evidence for adipose-derived stem cell therapy on the treatment of osteoarthritis.
      However, adverse reactions, consisting primarily of pain and swelling at the injection site, were reported in 5% of cases.

      Vitamin D

      An investigation by Sanghi et al.
      • Sanghi D.
      • Mishra A.
      • Sharma A.C.
      • et al.
      Does vitamin D improve osteoarthritis of the knee: A randomized controlled pilot trial.
      reported on 107 patients with knee OA and vitamin D insufficiency, randomized to treatment with 60,000 IU oral vitamin D daily for 10 days, followed by 60,000 IU once a month, versus placebo. At 12-month follow-up, significant biochemical changes in serum total vitamin D3 and alkaline phosphatases were observed in patients treated with vitamin D supplementation, with a small but statistically significant improvement in VAS and WOMAC scores compared with patients receiving placebo.
      It remains unknown whether vitamin D supplementation delays the progression of OA or produces a clinically significant effect on pain and function.
      • Liu X.
      • Machado G.C.
      • Eyles J.P.
      • Ravi V.
      • Hunter D.J.
      Dietary supplements for treating osteoarthritis: A systematic review and meta-analysis.
      McAlindon et al.
      • McAlindon T.
      • LaValley M.
      • Schneider E.
      • et al.
      Effect of vitamin D supplementation on progression of knee pain and cartilage volume loss in patients with symptomatic osteoarthritis: A randomized controlled trial.
      observed no improvement in knee function or reduction of cartilage volume loss in patients receiving 2000 IU vitamin D daily with dose escalation to elevate serum levels to >36 ng/ml. Meanwhile, Arden et al.
      • Arden N.K.
      • Cro S.
      • Sheard S.
      • et al.
      The effect of vitamin D supplementation on knee osteoarthritis, the VIDEO study: A randomised controlled trial.
      reported no significant improvement in pain, function, or delay of joint space narrowing in patients administered 800 IU of vitamin D daily. Similarly, Jin et al.
      • Jin X.
      • Jones G.
      • Cicuttini F.
      • et al.
      Effect of vitamin D supplementation on tibial cartilage volume and knee pain among patients with symptomatic knee osteoarthritis: A randomized clinical trial.
      observed no improvement in WOMAC knee pain or reduction of cartilage volume loss in patients consuming 50,000 IU vitamin D monthly (Table 3).
      Table 3Dietary supplements for Osteoarthritis—Clinical Studies Summary
      StudyLOEYear of PublicationType of InterventionAdjunctive to Surgery (Y/N)Sample SizeIntervention DetailsFollow-Up (mo)Favorable Outcome (Y/N)Results Summary
      Test GroupControl GroupTest GroupControl Group
      Sanghi et al
      • Sanghi D.
      • Mishra A.
      • Sharma A.C.
      • et al.
      Does vitamin D improve osteoarthritis of the knee: A randomized controlled pilot trial.
      I2013Vitamin DN5152Cholecalciferol 60,000 IU daily for 10 d followed by 60,000 IU monthly for 12 moPlacebo12YSmall improvement in VAS and WOMAC
      McAlindon et al
      • McAlindon T.
      • LaValley M.
      • Schneider E.
      • et al.
      Effect of vitamin D supplementation on progression of knee pain and cartilage volume loss in patients with symptomatic osteoarthritis: A randomized controlled trial.
      I2013Vitamin DN7373Cholecalciferol 2000 IU daily with dose escalation to elevate serum levels to >36 ng/mlPlacebo24NNo improvement in knee function or reduction of cartilage volume loss in patients with vitamin D supplementation
      Arden
      • Arden N.K.
      • Cro S.
      • Sheard S.
      • et al.
      The effect of vitamin D supplementation on knee osteoarthritis, the VIDEO study: A randomised controlled trial.
      I2016Vitamin DN188198Cholecalciferol 800 IU dailyPlacebo36NNo significant improvement in pain or function or delay of joint space narrowing in patients with vitamin D supplementation
      Jin
      • Jin X.
      • Jones G.
      • Cicuttini F.
      • et al.
      Effect of vitamin D supplementation on tibial cartilage volume and knee pain among patients with symptomatic knee osteoarthritis: A randomized clinical trial.
      I2016Vitamin DN209204Cholecalciferol 5000 IU monthlyPlacebo24NNo improvement in WOMAC knee pain nor reduction of cartilage volume loss in patients with vitamin D supplementation
      LOE, level of evidence; VAS, visual analog score; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

      Pathology of the Meniscus

      Brief overview

      Injuries to the meniscus represent the most common pathology treated by orthopaedic surgeons, with ≤61% of patients possessing pathology on imaging.
      • Englund M.
      • Lohmander L.S.
      Risk factors for symptomatic knee osteoarthritis fifteen to twenty-two years after meniscectomy.
      ,
      • Garrett W.E.J.
      • Swiontkowski M.F.
      • Weinstein J.N.
      • et al.
      American Board of Orthopaedic Surgery Practice of the Orthopaedic Surgeon: Part-II, certification examination case mix.
      Meniscal injuries are associated with decreased function and adverse changes in knee contact kinematics, increasing the risk for chondral injury and degeneration.
      • Abrams G.D.
      • Frank R.M.
      • Gupta A.K.
      • Harris J.D.
      • McCormick F.M.
      • Cole B.J.
      Trends in meniscus repair and meniscectomy in the United States, 2005-2011.
      ,
      • Eberbach H.
      • Zwingmann J.
      • Hohloch L.
      • et al.
      Sport-specific outcomes after isolated meniscal repair: A systematic review.
      Partial and total meniscectomy have been shown to result in higher contact pressures within the knee,
      • Ode G.E.
      • van Thiel G.S.
      • McArthur S.A.
      • et al.
      Effects of serial sectioning and repair of radial tears in the lateral meniscus.
      • Beamer B.S.
      • Walley K.C.
      • Okajima S.
      • et al.
      Changes in contact area in meniscus horizontal cleavage tears subjected to repair and resection.
      • LaPrade C.M.
      • Jansson K.S.
      • Dornan G.
      • Smith S.D.
      • Wijdicks C.A.
      • LaPrade R.F.
      Altered tibiofemoral contact mechanics due to lateral meniscus posterior horn root avulsions and radial tears can be restored with in situ pull-out suture repairs.
      leading to increased emphasis on meniscal preservation through meniscal repair.
      • Abrams G.D.
      • Frank R.M.
      • Gupta A.K.
      • Harris J.D.
      • McCormick F.M.
      • Cole B.J.
      Trends in meniscus repair and meniscectomy in the United States, 2005-2011.
      ,
      • Eberbach H.
      • Zwingmann J.
      • Hohloch L.
      • et al.
      Sport-specific outcomes after isolated meniscal repair: A systematic review.
      ,
      • Nepple J.J.
      • Dunn W.R.
      • Wright R.W.
      Meniscal repair outcomes at greater than five years: A systematic literature review and meta-analysis.
      ,
      • Xu C.
      • Zhao J.
      A meta-analysis comparing meniscal repair with meniscectomy in the treatment of meniscal tears: The more meniscus, the better outcome?.
      However, relatively high repair failure rates have been reported,
      • Stein T.
      • Mehling A.P.
      • Welsch F.
      • von Eisenhart-Rothe R.
      • Jäger A.
      Long-term outcome after arthroscopic meniscal repair versus arthroscopic partial meniscectomy for traumatic meniscal tears.
      ,
      • Paxton E.S.
      • Stock M v
      • Brophy R.H.
      Meniscal repair versus partial meniscectomy: A systematic review comparing reoperation rates and clinical outcomes.
      attributed to the unfavorable healing environment within the knee (Table 4).
      • de Albornoz P.M.
      • Forriol F.
      The meniscal healing process.
      Table 4Regenerative Therapy for Meniscus Pathology—Clinical Studies Summary
      StudyLOEYear of PublicationType of InterventionAdjunctive to Surgery (Y/N)Sample SizeIntervention DetailsFollow-Up (mo)Favorable Outcome (Y/N)Results Summary
      Test GroupControl GroupTest GroupControl Group
      van Trommel et al.
      • van Trommel M.F.
      • Simonian P.T.
      • Potter H.G.
      • Wickiewicz T.L.
      Arthroscopic meniscal repair with fibrin clot of complete radial tears of the lateral meniscus in the avascular zone.
      IV1998Fibrin clot with meniscus repairY5n/aFibrin clotn/aOnly 3/5 followed up (average 71 mo)Y5 patients treated with fibrin clot and meniscus repair demonstrated healing on second-look arthroscopy, with all patients returning to prior level of activity
      Ra et al.
      • Ra H.J.
      • Ha J.K.
      • Jang S.H.
      • Lee D.W.
      • Kim J.G.
      Arthroscopic inside-out repair of complete radial tears of the meniscus with a fibrin clot.
      Iv2013Fibrin clot with meniscus repairY12n/aFibrin clotn/aAverage 30-mo follow-upY12 patients treated with fibrin clot and meniscus repair demonstrated improved Lysholm and IKDC scores and healing on MRI
      Kamimurai et al.
      • Kamimura T.
      • Kimura M.
      Meniscal Repair of degenerative horizontal cleavage tears using fibrin clots: Clinical and arthroscopic outcomes in 10 cases.
      IV2014Fibrin clot with meniscus repairY10n/aFibrin clotn/aAverage 41-mo follow-upY10 patients treated with fibrin clot and meniscus repair report improved Lysholm and IKDC scores and healing on MRI
      Blanke et al
      • Blanke F.
      • Vavken P.
      • Haenle M.
      • von Wehren L.
      • Pagenstert G.
      • Majewski M.
      Percutaneous injections of platelet rich plasma for treatment of intrasubstance meniscal lesions.
      iV2015PRPN10n/aPRPn/a6YSignificant improvement in average pain rating scale score at 6-mo follow-up
      Kaminski et al.
      • Kaminski R.
      • Kulinski K.
      • Kozar-Kaminska K.
      • et al.
      A prospective, randomized, double-blind, parallel-group, placebo-controlled study evaluating meniscal healing, clinical outcomes, and safety in patients undergoing meniscal repair of unstable, complete vertical meniscal tears (bucket handle) augmented with platelet-rich plasma.
      I2014PRP + Meniscal repairY1918PRPSaline42YPRP injection at the time of meniscal repair led to significant meniscal healing in on second-look arthroscopy and MRI
      Piontek et al.
      • Piontek T.
      • Ciemniewska-Gorzela K.
      • Naczk J.
      • et al.
      Complex meniscus tears treated with collagen matrix wrapping and bone marrow blood injection: A 2-year clinical follow-up.
      IV2016BMAC + collagen wrapping + meniscal repairY53n/aBMAC + Collagen wrappingn/a24YSignificant improved in clinical outcomes with evidence of decrease rate of meniscal re-tearing on MRI
      Vangsness et al.
      • Vangsness C.T.J.
      • Farr 2nd, J.
      • Boyd J.
      • Dellaero D.T.
      • Mills C.R.
      • LeRoux-Williams M.
      Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy: A randomized, double-blind, controlled study.
      I2014BM-derived allogeneic MSCY3619MSC 50x10ˆ6 (18) MSC 150x10ˆ6 (18)Sodium hyaluronate (19)12YSignificantly increased meniscal volume (defined a priori as a 15% threshold) determined by quantitative MRI in MSC group 12 mo after meniscectomy
      BMAC, bone marrow aspirate concentrate; IKDC, International Knee Documentation Committee; LOE, level of evidence; MRI, magnetic resonance imaging; MSC, mesenchymal stromal cell; n/a, not applicable; PRP, platelet-rich plasma.

      Fibrin Clot

      An early investigation
      • van Trommel M.F.
      • Simonian P.T.
      • Potter H.G.
      • Wickiewicz T.L.
      Arthroscopic meniscal repair with fibrin clot of complete radial tears of the lateral meniscus in the avascular zone.
      examined 5 patients with complete radial tears of the lateral meniscus treated with repair and a fibrin clot. Second-look arthroscopy found that all repairs demonstrated healing at the periphery, with all patients returning to their prior level of activity. Ra et al.
      • Ra H.J.
      • Ha J.K.
      • Jang S.H.
      • Lee D.W.
      • Kim J.G.
      Arthroscopic inside-out repair of complete radial tears of the meniscus with a fibrin clot.
      reported on 12 patients with complete radial tears of the meniscus undergoing arthroscopic inside-out repair with fibrin clots. Improvements in Lysholm and IKDC subjective knee scores were reported at a mean of 30 ± 4 months, and 11 of 12 cases demonstrated complete healing based on MRI, along with complete healing in 6 of 7 patients undergoing second-look arthroscopy. Kamimura et al.
      • Kamimura T.
      • Kimura M.
      Meniscal Repair of degenerative horizontal cleavage tears using fibrin clots: Clinical and arthroscopic outcomes in 10 cases.
      reported that in 10 patients undergoing repair, significant improvements were reported based on mean Lysholm and IKDC scores at mean follow up of 40.8 ± 5.4 months, and second-look arthroscopy demonstrated complete healing in 70% of patients.

      Platelet-Rich Plasma

      Blanke et al.
      • Blanke F.
      • Vavken P.
      • Haenle M.
      • von Wehren L.
      • Pagenstert G.
      • Majewski M.
      Percutaneous injections of platelet rich plasma for treatment of intrasubstance meniscal lesions.
      reported that in 10 recreational athletes with intrasubstance meniscal lesions treated using percutaneous intrameniscal injections of PRP, significant improvement in average pain rating scale score were appreciated at 6-month follow-up.
      Augmentation of meniscal repair with PRP has been more widely reported.
      • Belk J.W.
      • Kraeutler M.J.
      • Thon S.G.
      • Littlefield C.P.
      • Smith J.H.
      • McCarty E.C.
      Augmentation of meniscal repair with platelet-rich plasma: A systematic review of comparative studies.
      A systematic review of 6 studies including 309 patients undergoing meniscal repair + PRP augmentation versus 445 patients treated with repair alone reported repair failures in 17% of patients with PRP versus 22.1% of patients without PRP at a mean follow-up of 32.8 months.
      • Belk J.W.
      • Kraeutler M.J.
      • Thon S.G.
      • Littlefield C.P.
      • Smith J.H.
      • McCarty E.C.
      Augmentation of meniscal repair with platelet-rich plasma: A systematic review of comparative studies.
      Kaminski et al.
      • Kaminski R.
      • Kulinski K.
      • Kozar-Kaminska K.
      • et al.
      A prospective, randomized, double-blind, parallel-group, placebo-controlled study evaluating meniscal healing, clinical outcomes, and safety in patients undergoing meniscal repair of unstable, complete vertical meniscal tears (bucket handle) augmented with platelet-rich plasma.
      reported significant improvements in patients receiving PRP + repair versus repairs alone. Meniscal healing, evaluated on second-look arthroscopy or MRI, was present in 85% of repairs augmented with PRP versus 47% in the non-PRP group (P = .048).
      • Jin X.
      • Jones G.
      • Cicuttini F.
      • et al.
      Effect of vitamin D supplementation on tibial cartilage volume and knee pain among patients with symptomatic knee osteoarthritis: A randomized clinical trial.
      The systematic review conducted by Sochacki et al.
      • Sochacki K.R.
      • Safran M.R.
      • Abrams G.D.
      • Donahue J.
      • Chu C.
      • Sherman S.L.
      Platelet-rich plasma augmentation for isolated arthroscopic meniscal repairs leads to significantly lower failure rates: A systematic review of comparative studies.
      consisting of 5 articles analyzing 110 patients treated with PRP + meniscal repair versus 164 with repair alone reported that repairs augmented with PPR had a significantly lower failure rate (range 4.4% to 26.7%) compared with repairs without PRP (range 13.3% to 50%; P = .03). The conflicting results in healing rates and PROs can be attributed largely to the differences in PRP formulation, with variable concentrations of platelets, leukocytes, and growth factors.
      • Belk J.W.
      • Kraeutler M.J.
      • Thon S.G.
      • Littlefield C.P.
      • Smith J.H.
      • McCarty E.C.
      Augmentation of meniscal repair with platelet-rich plasma: A systematic review of comparative studies.

      Bone Marrow Aspirate Concentrate

      A basic science investigation
      • Koch M.
      • Hammer S.
      • Fuellerer J.
      • et al.
      Bone marrow aspirate concentrate for the treatment of avascular meniscus tears in a one-step procedure-evaluation of an in vivo model.
      using a rabbit model with avascular meniscal lesions reported that repairs augmented with BMAC led to superior macroscopic and histologic healing compared with specimens treated with repair + PRP or repair alone at 6 and 12 weeks. Use of BMAC and collagen wrapping for repaired meniscal lesions in 50 consecutive patients led significant improvement in clinical outcomes at 2-year follow-up, and postoperative MRI demonstrated no evidence of meniscal re-tearing in 76% of menisci.
      • Piontek T.
      • Ciemniewska-Gorzela K.
      • Naczk J.
      • et al.
      Complex meniscus tears treated with collagen matrix wrapping and bone marrow blood injection: A 2-year clinical follow-up.

      Mesenchymal Stromal Cells

      A randomized, double-blind controlled study
      • Vangsness C.T.J.
      • Farr 2nd, J.
      • Boyd J.
      • Dellaero D.T.
      • Mills C.R.
      • LeRoux-Williams M.
      Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy: A randomized, double-blind, controlled study.
      evaluated 55 patients undergoing partial meniscectomy 7 to 10 days after surgery with injection of either 50 million (group A) or 150 million (group B) bone-marrow–derived allogeneic MSCs suspended in a sodium hyaluronate solution compared with patients undergoing injection with the suspension alone (group C).
      • Vangsness C.T.J.
      • Farr 2nd, J.
      • Boyd J.
      • Dellaero D.T.
      • Mills C.R.
      • LeRoux-Williams M.
      Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy: A randomized, double-blind, controlled study.
      Significant meniscal volume gain on MRI was reported in 24% of patients in group A, 6% of patients in group B, and no patients in group C. A prospective case study reported on a series of 5 patients with bone marrow–derived MSCs placed onto a collagen scaffold arthroscopically implanted before meniscal repair using sutures.
      • Chan B.P.
      • Fu S.
      • Qin L.
      • Lee K.
      • Rolf C.G.
      • Chan K.
      Effects of basic fibroblast growth factor (bFGF) on early stages of tendon healing: A rat patellar tendon model.
      At 24-month follow-up, clinical improvements were reported in Tegner, Lysholm, and IKDC scores; however, 2 patients required subsequent partial meniscectomy. A systematic review of 4 studies evaluating the use of MSCs for meniscal regeneration
      • Chew E.
      • Prakash R.
      • Khan W.
      Mesenchymal stem cells in human meniscal regeneration: A systematic review.
      reported that despite improvements in VAS score, marked differences in stem cell harvest method (bone marrow autograft, n = 2; bone marrow allograft, n = 1; fat-derived via liposuction, n = 1) and route of administration (percutaneous injection, n = 3; collagen scaffold, n = 1) were recorded.
      • Chew E.
      • Prakash R.
      • Khan W.
      Mesenchymal stem cells in human meniscal regeneration: A systematic review.

      Tendon Pathology

      Brief Overview

      Disease and injury to tendons account for 30% to 50% of all musculoskeletal injuries.
      • Wu F.
      • Nerlich M.
      • Docheva D.
      Tendon injuries: Basic science and new repair proposals.
      ,
      • Ho J.O.
      • Sawadkar P.
      • Mudera V.
      A review on the use of cell therapy in the treatment of tendon disease and injuries.
      Tendon pathology ranges from acute tears to chronic degenerative overuse.
      • Sprague A.
      • Epsley S.
      • Silbernagel K.G.
      Distinguishing quadriceps tendinopathy and patellar tendinopathy: Semantics or significant?.
      ,
      • Ramseier L.E.
      • Werner C.M.L.
      • Heinzelmann M.
      Quadriceps and patellar tendon rupture.
      Treatment is largely determined by the specific tendons involved, location (intratendinous versus myotendinous), and timing (acute versus chronic).
      • Piuzzi N.S.
      • Dominici M.
      • Long M.
      • et al.
      Proceedings of the signature series symposium “Cellular therapies for orthopaedics and musculoskeletal disease proven and unproven therapies-promise, facts and fantasy,” International Society for Cellular Therapies, Montreal, Canada, May 2, 2018.
      In the setting of acute tears, treatment is aimed at promoting cellular proliferation and healing, whereas chronic tendinopathy is managed by targeting inflammatory mediators and inhibiting matrix-degrading proteinases to improve healing (Table 5).
      • Piuzzi N.S.
      • Dominici M.
      • Long M.
      • et al.
      Proceedings of the signature series symposium “Cellular therapies for orthopaedics and musculoskeletal disease proven and unproven therapies-promise, facts and fantasy,” International Society for Cellular Therapies, Montreal, Canada, May 2, 2018.
      Table 5Regenerative therapy for tendon pathology—clinical studies summary
      StudyLOEYear of PublicationType of InterventionAdjunctive to Surgery (Y/N)Sample SizeIntervention DetailsFollow-Up (mo)Favorable Outcome (Y/N)Results Summary
      Test GroupControl GroupTest GroupControl Group
      Muneta et al.
      • Muneta T.
      • Koga H.
      • Ju Y.-J.
      • Mochizuki T.
      • Sekiya I.
      Hyaluronan injection therapy for athletic patients with patellar tendinopathy.
      IV2012HAN50noneHAnone6-88Y54% return to previous athletic activities with little difficulty and 40% return to previous sporting activities with some degree of limitation
      Dragoo et al.
      • Dragoo J.L.
      • Wasterlain A.S.
      • Braun H.J.
      • Nead K.T.
      Platelet-rich plasma as a treatment for patellar tendinopathy: A double-blind, randomized controlled trial.
      I2014LR-PRP with dry needlingN1012LR- PRPDry needling3YSignificant improvement in VISA-P score with PRP at 12 wk
      Vetrano et al
      • Vetrano M.
      • Castorina A.
      • Vulpiani M.C.
      • Baldini R.
      • Pavan A.
      • Ferretti A.
      Platelet-rich plasma versus focused shock waves in the treatment of jumper’s knee in athletes.
      I2013PRPN2323PRP ×2 injectionsESWT12YSignificant better improvement of VISA-P and VAS scores at 6- and 12-mo follow-up and modified Blazina scale score at 12-mo follow-up with PRP
      Scott et al.
      • Scott A.
      • LaPrade R.F.
      • Harmon K.G.
      • et al.
      Platelet-rich plasma for patellar tendinopathy: A randomized controlled trial of leukocyte-rich PRP or leukocyte-poor PRP versus saline.
      I2019LR-PRPN3619LR-PRP (19); LP-PRP (19)Saline (19)12NSingle injection of LR-PRP or LP-PRP was no more effective than saline for the improvement of patellar tendinopathy symptoms
      Pascual-Garrido et al.
      • Pascual-Garrido C.
      • Rolón A.
      • Makino A.
      Treatment of chronic patellar tendinopathy with autologous bone marrow stem cells: A 5-year-followup.
      IV2012BM-MNCN8NoneBM-MNCNone60YSignificant improvement in most clinical scores at yearly follow-up with use of BM-MNCs
      Clarke et al.
      • Clarke A.W.
      • Alyas F.
      • Morris T.
      • Robertson C.J.
      • Bell J.
      • Connell D.A.
      Skin-derived tenocyte-like cells for the treatment of patellar tendinopathy.
      I2010Skin-derived tenocyte-like collagen-producing cellsN2323TDSC + PRPPRP alone6YSignificantly higher VISA scores at 6-mo follow-up in patients receiving skin-derived tenocyte-like collagen-producing cell
      BM, bone marrow; ESWT, extracorporeal shockwave therapy; HA, hyaluronic acid; LOE, level of evidence; LP, leukocyte-poor; LR, leukocyte-rich; MNC, mononuclear cell; PRP, platelet-rich plasma; TDSC, tendon-derived stem cell; VAS, visual analog score; VISA-P, Victorian Institute of Sports Assessment – Pain.

      Hyaluronic Acid

      HA has been shown to increase tenocyte viability and type collagen I production and deposition and reduce the surface friction of tendons.
      • Fogli M.
      • Giordan N.
      • Mazzoni G.
      Efficacy and safety of hyaluronic acid (500-730kDa) ultrasound-guided injections on painful tendinopathies: A prospective, open label, clinical study.
      • Wiig M.
      • Abrahamsson S.O.
      • Lundborg G.
      Effects of hyaluronan on cell proliferation and collagen synthesis: A study of rabbit flexor tendons in vitro.
      • Abate M.
      • Schiavone C.
      • Salini V.
      The use of hyaluronic acid after tendon surgery and in tendinopathies.
      • Akasaka T.
      • Nishida J.
      • Araki S.
      • Shimamura T.
      • Amadio P.C.
      • An K.-N.
      Hyaluronic acid diminishes the resistance to excursion after flexor tendon repair: An in vitro biomechanical study.
      • Kolodzinskyi M.N.
      • Zhao C.
      • Sun Y.-L.
      • et al.
      The effects of hylan g-f 20 surface modification on gliding of extrasynovial canine tendon grafts in vitro.
      A prospective study investigating outcomes after a single injection of HA to the patellar tendon with 1-week follow-up reported significant improvement in VAS pain score.
      • Kumai T.
      • Muneta T.
      • Tsuchiya A.
      • et al.
      The short-term effect after a single injection of high-molecular-weight hyaluronic acid in patients with enthesopathies (lateral epicondylitis, patellar tendinopathy, insertional Achilles tendinopathy, and plantar fasciitis): A preliminary study.
      Similarly, 50 patients with patellar tendinopathy (Blazina grade 2 to 3) reported good to excellent outcomes at a mean follow-up of 25.7 months after an average of 2 HA injections.
      • Muneta T.
      • Koga H.
      • Ju Y.-J.
      • Mochizuki T.
      • Sekiya I.
      Hyaluronan injection therapy for athletic patients with patellar tendinopathy.

      Platelet-Rich Plasma

      An RCT comparing LR-PRP to dry needling for patellar tendinopathy reported improvement in both groups, with significant improvement in Victorian Institute of Sports Assessment—Pain (VISA-P) score with PRP at 12 weeks (P = .02).
      • Dragoo J.L.
      • Wasterlain A.S.
      • Braun H.J.
      • Nead K.T.
      Platelet-rich plasma as a treatment for patellar tendinopathy: A double-blind, randomized controlled trial.
      Another RCT of 46 patients with patellar tendinopathy comparing PRP injections versus focused extracorporeal shockwave therapy in athletes reported no significant differences between groups at 2-month follow-up.
      • Vetrano M.
      • Castorina A.
      • Vulpiani M.C.
      • Baldini R.
      • Pavan A.
      • Ferretti A.
      Platelet-rich plasma versus focused shock waves in the treatment of jumper’s knee in athletes.
      However, significant improvement in VISA-P and VAS scores at 6- and 12-month follow-up were recorded in the PRP group. Several other studies, albeit of lower evidence, have supported the use of PRP for knee tendinopathies.
      • Charousset C.
      • Zaoui A.
      • Bellaiche L.
      • Bouyer B.
      Are multiple platelet-rich plasma injections useful for treatment of chronic patellar tendinopathy in athletes? A prospective study.
      ,
      • Filardo G.
      • Kon E.
      • di Matteo B.
      • Pelotti P.
      • di Martino A.
      • Marcacci M.
      Platelet-rich plasma for the treatment of patellar tendinopathy: Clinical and imaging findings at medium-term follow-up.
      Meanwhile, a RCT by Scott et al.
      • Scott A.
      • LaPrade R.F.
      • Harmon K.G.
      • et al.
      Platelet-rich plasma for patellar tendinopathy: A randomized controlled trial of leukocyte-rich PRP or leukocyte-poor PRP versus saline.
      compared LR-PRP versus normal saline injections in athletes with patellar tendinopathy for >6 months. No significant differences in VISA-P, pain, or global rating of change were reported between treatment groups. There remains a paucity of evidence regarding outcomes when PRP is used as an adjuvant for patellar tendon surgery, although patellar tendon tenotomy with subsequent repair and PRP injection for recalcitrant tendinopathy has been described.
      • Kruckeberg B.M.
      • Chahla J.
      • Ferrari M.B.
      • Sanchez G.
      • Moatshe G.
      • LaPrade R.F.
      Open patellar tendon tenotomy, debridement, and repair technique augmented with platelet-rich plasma for recalcitrant patellar tendinopathy.

      Bone Marrow Aspirate Concentrate

      A retrospective case series
      • Pascual-Garrido C.
      • Rolón A.
      • Makino A.
      Treatment of chronic patellar tendinopathy with autologous bone marrow stem cells: A 5-year-followup.
      reporting on 8 patients with refractory patellar tendinopathy treated with BMAC reported statistically significant improvement in most clinical scores at yearly follow-up, starting at 12 months. At final follow-up (range 24 to 60 months), 7 of 8 patients reported they would undergo the procedure again.

      Mesenchymal Stromal Cells

      A preclinical study using a rabbit model with a patellar tendon defect in the central portion of the patellar tendon examined the use of tendon-derived stem cells (TDSCs) + fibrin compared with fibrin alone.
      • Ni M.
      • Lui P.P.Y.
      • Rui Y.F.
      • et al.
      Tendon-derived stem cells (TDSCs) promote tendon repair in a rat patellar tendon window defect model.
      Significantly higher ultimate stress and Young’s modulus was reported in the TDSC group, concluding that the use of TDSCs promoted earlier and improved tendon repair. A double-blind study of 60 knees in 46 patients with refractory patellar tendinopathy reported significantly higher VISA scores at 6-month follow-up in patients receiving skin-derived tenocyte-like collagen-producing cells versus autologous plasma, with histopathology showing normal tendon structure.
      • Clarke A.W.
      • Alyas F.
      • Morris T.
      • Robertson C.J.
      • Bell J.
      • Connell D.A.
      Skin-derived tenocyte-like cells for the treatment of patellar tendinopathy.

      Pathology of the Ligaments

      Brief Overview

      Ligament injuries account for approximately 40% of all knee injuries.
      • Mack C.D.
      • Kent R.W.
      • Coughlin M.J.
      • et al.
      Incidence of lower extremity injury in the National Football League: 2015 to 2018.
      ,

      Posch M, Schranz A, Lener M, Tecklenburg K, Burtscher M, Ruedl G. In recreational alpine skiing, the ACL is predominantly injured in all knee injuries needing hospitalisation. Knee Surg Sports Traumatol Arthrosc. Online ahead of print.

      Injuries often result in recurrent instability, muscle weakness, and reduced functional performance, with long-term clinical sequelae including meniscal tears, chondral lesions, and increased risk of early-onset post-traumatic OA. Injuries most commonly involve the medial collateral ligament (MCL) and anterior cruciate ligament (ACL).
      • Hewett T.E.
      • di Stasi S.L.
      • Myer G.D.
      Current concepts for injury prevention in athletes after anterior cruciate ligament reconstruction.
      MCL injuries are most commonly treated with early mobilization and nonoperative management,
      • Lyon R.M.
      • Akeson W.H.
      • Amiel D.
      • Kitabayashi L.R.
      • Woo S.L.
      Ultrastructural differences between the cells of the medical collateral and the anterior cruciate ligaments.
      whereas ACL injuries possess poor healing capacity with potential for failure after reconstruction.
      • Strand T.
      • Mølster A.
      • Hordvik M.
      • Krukhaug Y.
      Long-term follow-up after primary repair of the anterior cruciate ligament: Clinical and radiological evaluation 15-23 years postoperatively.
      • Hefti F.L.
      • Kress A.
      • Fasel J.
      • Morscher E.W.
      Healing of the transected anterior cruciate ligament in the rabbit.
      • O’Donoghue D.H.
      • Rockwood C.A.J.
      • Frank G.R.
      • Jack S.C.
      • Kenyon R.
      Repair of the anterior cruciate ligament in dogs.
      Biological strategies have been proposed for both conservative treatment and augmentation during ACL reconstruction to promote graft maturation and osteoligamentous graft integration (Table 6).
      • di Matteo B.
      • Loibl M.
      • Andriolo L.
      • et al.
      Biologic agents for anterior cruciate ligament healing: A systematic review.
      Table 6Regenerative Therapy for Ligament Pathology - Clinical Studies Summary


      Study
      LOEYear of PublicationType of InterventionAdjunctive to Surgery (Y/N)Sample SizeIntervention DetailsFollow up (months)Favorable Outcome (Y/N)Results Summary
      Test GroupControlTest GroupControl
      Seijas et al.
      • Seijas R.
      • Ares O.
      • Cuscó X.
      • Alvarez P.
      • Steinbacher G.
      • Cugat R.
      Partial anterior cruciate ligament tears treated with intraligamentary plasma rich in growth factors.
      IV2014PRGFN19nonePRGFnone24YHigh return to sport rates at pre- injury level in professional football players treated with PRGF


      Koch et al.
      • Koch M.
      • Mayr F.
      • Achenbach L.
      • et al.
      Partial anterior cruciate ligament ruptures: Advantages by intraligament autologous conditioned plasma injection and healing response technique—Midterm outcome evaluation.


      IV
      2018PRPN42nonePRPnone24YSignificantly improved IKDC, Lysholm, Tegner, and Cincinnati scores w/ PRP


      Sanchez et al.
      • Sánchez M.
      • Anitua E.
      • Azofra J.
      • Prado R.
      • Muruzabal F.
      • Andia I.
      Ligamentization of tendon grafts treated with an endogenous preparation rich in growth factors: Gross morphology and histology.


      III
      2010PRGF + ACL-RY2215PRGFACL-R alone12YSignificantly improved connective tissue after PRGF augmented ACL-R on histologic evaluation
      Radice et al
      • Radice F.
      • Yánez R.
      • Gutiérrez V.
      • Rosales J.
      • Pinedo M.
      • Coda S.
      Comparison of magnetic resonance imaging findings in anterior cruciate ligament grafts with and without autologous platelet-derived growth factors.
      III2010PRPG + ACL-RY2525PRPGACL-R alone12YFaster complete homogeneous grafts assessed by MRI w/ PRPG + ACL-R
      Berdis et al.
      • Berdis A.S.
      • Veale K.
      • Fleissner P.R.J.
      Outcomes of anterior cruciate ligament reconstruction using biologic augmentation in patients 21 years of age and younger.
      IV2019PRP + ACL-RY151none151n/a25 - 94 monthsYSignificant decrease rate decreased rate of second ACL injury w/ high return to preinjury level of competition
      Centeno et al.
      • Centeno C.J.
      • Pitts J.
      • Al-Sayegh H.
      • Freeman M.D.
      Anterior cruciate ligament tears treated with percutaneous injection of autologous bone marrow nucleated cells: A case series.
      IV2015BMAC + PRPN10none10none2.5 - 7 monthsYSeven of 10 patients showed improved ACL integrity based on postoperative MRI and improved mean VAS and Lower Extremity Functional Scale scores
      Alentorn-Geli et al.
      • Alentorn-Geli E.
      • Seijas R.
      • Martínez-De la Torre A.
      • et al.
      Effects of autologous adipose-derived regenerative stem cells administered at the time of anterior cruciate ligament reconstruction on knee function and graft healing.
      III2019ADRC + ACL-RY2019ADRCACL-R alone12NImprovement w/ ADRC was not statistically different from ACL reconstruction alone
      ACL-R, Anterior Cruciate Ligament Reconstruction; ADRC Adipose Derived Rich l Stem Cells; BMAC, Bone Marrow Aspirate Concentrate; IKDC, International Knee Documentation Knee; MRI, Magnetic Resonance Imaging; PRGF, Platelet Rich Growth Factors; PRP, Platelet Rich Plasma.

      Platelet-Rich Plasma

      Seijas et al.
      • Seijas R.
      • Ares O.
      • Cuscó X.
      • Alvarez P.
      • Steinbacher G.
      • Cugat R.
      Partial anterior cruciate ligament tears treated with intraligamentary plasma rich in growth factors.
      reported on intraligamentous administration of 4 mL PRP product (PRGF-Endoret)
      • Anitua E.
      Plasma rich in growth factors: Preliminary results of use in the preparation of future sites for implants.
      in 19 professional soccer athletes with partial ACL tears after reconstruction, with an additional 6 mL injected into the articular space after surgery. Eighteen athletes returned to their preinjury level of play.
      • Seijas R.
      • Ares O.
      • Cuscó X.
      • Alvarez P.
      • Steinbacher G.
      • Cugat R.
      Partial anterior cruciate ligament tears treated with intraligamentary plasma rich in growth factors.
      Koch et al.
      • Koch M.
      • Mayr F.
      • Achenbach L.
      • et al.
      Partial anterior cruciate ligament ruptures: Advantages by intraligament autologous conditioned plasma injection and healing response technique—Midterm outcome evaluation.
      reported improved IKDC, Lysholm, Tegner, and Cincinnati scores at a mean follow-up of 33 months after arthroscopic intraligamentous administration of autologous conditioned plasma in 42 patients with partial ACL tears using ACP injection and healing response technique.
      • Koch M.
      • Matteo B di
      • Eichhorn J.
      • et al.
      Intra-ligamentary autologous conditioned plasma and healing response to treat partial ACL ruptures.
      Despite promising results, neither study included a control group, making assessment of PRP on outcomes difficult to interpret.
      Histological evaluation of augmented grafts has shown newly formed connective tissue in 77.3% of the platelet-rich growth factor (PRGF)–assisted ACL grafts compared with 40% of nonaugmented grafts at a minimum of 6 months.
      • Sánchez M.
      • Anitua E.
      • Azofra J.
      • Prado R.
      • Muruzabal F.
      • Andia I.
      Ligamentization of tendon grafts treated with an endogenous preparation rich in growth factors: Gross morphology and histology.
      An RCT matched 25 patients treated with ACL reconstruction in combination with a platelet-rich plasma gel (PRPG) to a control group with reconstruction alone.
      • Radice F.
      • Yánez R.
      • Gutiérrez V.
      • Rosales J.
      • Pinedo M.
      • Coda S.
      Comparison of magnetic resonance imaging findings in anterior cruciate ligament grafts with and without autologous platelet-derived growth factors.
      Complete graft homogeneity was achieved by 179 days in the PRPG group compared with 369 days in the non-PRPG group, and maturation time was reduced from 12 months to 3.6 months in the PRGF group. A recent retrospective study of 143 patients <21 years of age reported decreased ACL reinjury rates requiring revision surgery in patients with ACL reconstruction coupled with PRP and a porous collagen carrier, with 132 of 143 patients returning to preinjury level.
      • Berdis A.S.
      • Veale K.
      • Fleissner P.R.J.
      Outcomes of anterior cruciate ligament reconstruction using biologic augmentation in patients 21 years of age and younger.

      Bone Marrow Aspirate Concentrate

      A case series reported on 10 patients with partial ACL tears treated with fluoroscopically guided intraligamentous injection of autologous BMAC + PRP.
      • Centeno C.J.
      • Pitts J.
      • Al-Sayegh H.
      • Freeman M.D.
      Anterior cruciate ligament tears treated with percutaneous injection of autologous bone marrow nucleated cells: A case series.
      Seven of the 10 patients showed improved ACL integrity based on postoperative MRI; improvements in mean VAS and Lower Extremity Functional Scale were also reported.

      Mesenchymal Stromal Cells

      Kanaya et al.
      • Kanaya A.
      • Deie M.
      • Adachi N.
      • Nishimori M.
      • Yanada S.
      • Ochi M.
      Intra-articular injection of mesenchymal stromal cells in partially torn anterior cruciate ligaments in a rat model.
      compared ACL healing using MSCs with phosphate-buffered solution versus phosphate-buffered solution alone in rats with partially torn ACL. The MSC group showed improved ligament healing, histologic features, and femur-ACL-tibia complex load-to-failure compared with controls. Recently, Alentorn-Geli et al.
      • Alentorn-Geli E.
      • Seijas R.
      • Martínez-De la Torre A.
      • et al.
      Effects of autologous adipose-derived regenerative stem cells administered at the time of anterior cruciate ligament reconstruction on knee function and graft healing.
      reported on clinical outcomes of 20 soccer athletes undergoing ACL reconstruction using bone-to-bone autograft augmented with adipose tissue and other progenitor cells, collectively termed adipose-derived regenerative stem cells. No significant differences were appreciated between the augmented group and a matched cohort (P > .05) at 12-month follow-up.

      Prospects for the Future

      Future investigations examining currently administered orthobiologics for the treatment of knee injuries require increasing focus on the standardization of solution preparations. Namely, the inconsistent results reported after orthobiologics use may be attributed to the heterogeneity of final HA, PRP, BMAC, and MSC preparations and injection regimens, largely limiting the ability to reliably and meaningfully compare outcomes between studies to determine the true efficacy and safety profiles for each treatment. As such, minimizing variability in processing and formulations is essential to advance the field of orthobiologics for orthoregeneration in patients with knee injuries. Meanwhile, further investigations evaluating the use of matrix-based cell therapies and vitamin supplementation are warranted to better understand their efficacy for the treatment of musculoskeletal disorders affecting the knee.

      Conclusion

      There remains increasing interest and tremendous potential for the use of orthobiologics for the treatment of various knee injuries and pathologies. Despite a number of available studies, there remain conflicting outcomes and no consensus regarding the optimal treatment for patients sustaining injuries to the cartilage, meniscus, tendon, or ligaments of the knee. Further high-quality comparative studies are warranted to analyze currently available orthobiologics therapies, while also promoting the importance of standardizing orthobiologic preparation methods and formulations.

      Supplementary Data

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