Biologic therapies, including stem cells, platelet-rich plasma, growth factors, and other biologically active adjuncts, have recently received increased attention in the basic science and clinical literature. At the 2015 AOSSM Biologics II Think Tank held in Colorado Springs, Colorado, a group of orthopaedic surgeons, basic scientists, veterinarians, and other investigators gathered to review the state of the science for biologics and barriers to implementation of biologics for the treatment of sports medicine injuries. This series of current concepts reviews reports the summary of the scientific presentations, roundtable discussions, and recommendations from this think tank.
AbateMSilbernagelKGSiljeholmC. Pathogenesis of tendinopathies: inflammation or degeneration?Arthritis Res Ther. 2009;11(3):235.
2.
AdamsMKGoodrichLRRaoS. Equine bone marrow-derived mesenchymal stromal cells (BMDMSCs) from the ilium and sternum: are there differences?Equine Vet J. 2013;45(3):372-375.
3.
AjuiedAWongFSmithC. Anterior cruciate ligament injury and radiologic progression of knee osteoarthritis: a systematic review and meta-analysis. Am J Sports Med. 2014;42(9):2242-2252.
4.
AkitaSAkinoKTanakaKAnrakuKHiranoA. A basic fibroblast growth factor improves lower extremity wound healing with a porcine-derived skin substitute. J Trauma. 2008;64(3):809-815.
5.
AndersonKSeneviratneAMIzawaKAtkinsonBLPotterHGRodeoSA. Augmentation of tendon healing in an intraarticular bone tunnel with use of a bone growth factor. Am J Sports Med. 2001;29(6):689-698.
6.
AndresBMMurrellGA. Treatment of tendinopathy: what works, what does not, and what is on the horizon. Clin Orthop Relat Res. 2008;466(7):1539-1554.
7.
AnzAWHackelJGNilssenECAndrewsJR. Application of biologics in the treatment of the rotator cuff, meniscus, cartilage, and osteoarthritis. J Am Acad Orthop Surg. 2014;22(2):68-79.
8.
ArnoczkySPWarrenRFAshlockMA. Replacement of the anterior cruciate ligament using a patellar tendon allograft. An experimental study. J Bone Joint Surg Am. 1986;68(3):376-385.
9.
AustLDevlinBFosterSJ. Yield of human adipose-derived adult stem cells from liposuction aspirates. Cytotherapy. 2004;6(1):7-14.
10.
BareniusBPonzerSShalabiABujakRNorlenLErikssonK. Increased risk of osteoarthritis after anterior cruciate ligament reconstruction: a 14-year follow-up study of a randomized controlled trial. Am J Sports Med. 2014;42(5):1049-1057.
11.
BarrackRLBrucknerJDKneislJInmanWSAlexanderAH. The outcome of nonoperatively treated complete tears of the anterior cruciate ligament in active young adults. Clin Orthop Relat Res. 1990;259:192-199.
12.
BentivegnaAMilosoMRivaG. DNA methylation changes during in vitro propagation of human mesenchymal stem cells: implications for their genomic stability?Stem Cells Int. 2013;2013:192425.
13.
BeyeJAHartDABrayRCMcDougallJJSaloPT. Injury-induced changes in mRNA levels differ widely between anterior cruciate ligament and medial collateral ligament. Am J Sports Med. 2008;36(7):1337-1346.
14.
BianchiFMaioliMLeonardiE. A new nonenzymatic method and device to obtain a fat tissue derivative highly enriched in pericyte-like elements by mild mechanical forces from human lipoaspirates. Cell Transplant. 2013;22(11):2063-2077.
15.
BonabMMAlimoghaddamKTalebianFGhaffariSHGhavamzadehANikbinB. Aging of mesenchymal stem cell in vitro. BMC Cell Biol. 2006;7:14.
16.
BraunHJKimHJChuCRDragooJL. The effect of platelet-rich plasma formulations and blood products on human synoviocytes: implications for intra-articular injury and therapy. Am J Sports Med. 2014;42(5):1204-1210.
17.
BunnellBABetancourtAMSullivanDE. New concepts on the immune modulation mediated by mesenchymal stem cells. Stem Cell Res Ther. 2010;1(5):34.
18.
CaplanAI. All MSCs are pericytes?Cell Stem Cell. 2008;3(3):229-230.
19.
CaplanAICorreaD. The MSC: an injury drugstore. Cell Stem Cell. 2011;9(1):11-15.
20.
CarrageeEJHurwitzELWeinerBK. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. Spine J. 2011;11(6):471-491.
21.
CastilloTNPouliotMAKimHJDragooJL. Comparison of growth factor and platelet concentration from commercial platelet-rich plasma separation systems. Am J Sports Med. 2011;39(2):266-271.
22.
CiuffiSFabbriSZonefratiR. P3 - human mesenchymal stem cells: isolation and concentration from bone marrow using the Regenkit device. Clin Cases Miner Bone Metab. 2010;7(3):209.
23.
ClaesSVerdonkPForsythRBellemansJ. The “ligamentization” process in anterior cruciate ligament reconstruction: what happens to the human graft? A systematic review of the literature. Am J Sports Med. 2011;39(11):2476-2483.
24.
CookJLPurdamCR. Is tendon pathology a continuum? A pathology model to explain the clinical presentation of load-induced tendinopathy. Br J Sports Med. 2009;43(6):409-416.
25.
CoppingerJACagneyGToomeyS. Characterization of the proteins released from activated platelets leads to localization of novel platelet proteins in human atherosclerotic lesions. Blood. 2004;103(6):2096-2104.
26.
CorselliMCrisanMMurrayIR. Identification of perivascular mesenchymal stromal/stem cells by flow cytometry. Cytometry A. 2013;83(8):714-720.
27.
CrisanMDeasyBGavinaM. Purification and long-term culture of multipotent progenitor cells affiliated with the walls of human blood vessels: myoendothelial cells and pericytes. Methods Cell Biol. 2008;86:295-309.
28.
de AlmeidaAMDemangeMKSobradoMFRodriguesMBPedrinelliAHernandezAJ. Patellar tendon healing with platelet-rich plasma: a prospective randomized controlled trial. Am J Sports Med. 2012;40(6):1282-1288.
29.
de VosRJWeirAvan SchieHT. Platelet-rich plasma injection for chronic Achilles tendinopathy: a randomized controlled trial. JAMA. 2010;303(2):144-149.
30.
DeanBJGettingsPDakinSGCarrAJ. Are inflammatory cells increased in painful human tendinopathy? A systematic review. Br J Sports Med. 2016;50(4):216-220.
31.
DominiciMLe BlancKMuellerI. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315-317.
32.
DragooJLBraunHJDurhamJL. Comparison of the acute inflammatory response of two commercial platelet-rich plasma systems in healthy rabbit tendons. Am J Sports Med. 2012;40(6):1274-1281.
33.
DragooJLSamimiBZhuM. Tissue-engineered cartilage and bone using stem cells from human infrapatellar fat pads. J Bone Joint Surg Br. 2003;85(5):740-747.
34.
DragooJLWasterlainASBraunHJNeadKT. Platelet-rich plasma as a treatment for patellar tendinopathy: a double-blind, randomized controlled trial. Am J Sports Med. 2014;42(3):610-618.
35.
FeaginJAJrCurlWW. Isolated tear of the anterior cruciate ligament: 5-year follow-up study. Am J Sports Med. 1976;4(3):95-100.
36.
FriedlaenderGEPerryCRColeJD. Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am. 2001;83(Suppl 1):S151-S158.
37.
GarrettWEJrSwiontkowskiMFWeinsteinJN. American Board of Orthopaedic Surgery Practice of the Orthopaedic Surgeon: Part-II, certification examination case mix. J Bone Joint Surg Am. 2006;88(3):660-667.
38.
GiustiIRughettiAD’AscenzoS. Identification of an optimal concentration of platelet gel for promoting angiogenesis in human endothelial cells. Transfusion. 2009;49(4):771-778.
39.
GoradiaVKRochatMCKidaMGranaWA. Natural history of a hamstring tendon autograft used for anterior cruciate ligament reconstruction in a sheep model. Am J Sports Med. 2000;28(1):40-46.
40.
GovenderSCsimmaCGenantHK. Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am. 2002;84(12):2123-2134.
41.
GranaWAEgleDMMahnkenRGoodhartCW. An analysis of autograft fixation after anterior cruciate ligament reconstruction in a rabbit model. Am J Sports Med. 1994;22(3):344-351.
42.
GuoXZhengQKulbatskiI. Bone regeneration with active angiogenesis by basic fibroblast growth factor gene transfected mesenchymal stem cells seeded on porous beta-TCP ceramic scaffolds. Biomed Mater. 2006;1(3):93-99.
43.
HernigouPFlouzat LachanietteCHDelambreJ. Biologic augmentation of rotator cuff repair with mesenchymal stem cells during arthroscopy improves healing and prevents further tears: a case-controlled study. Int Orthop. 2014;38(9):1811-1818.
44.
HuardJLiYFuFH. Muscle injuries and repair: current trends in research. J Bone Joint Surg Am. 2002;84(5):822-832.
45.
JamesAWZaraJNCorselliM. An abundant perivascular source of stem cells for bone tissue engineering. Stem Cells Transl Med. 2012;1(9):673-684.
46.
KannusPJozsaL. Histopathological changes preceding spontaneous rupture of a tendon. A controlled study of 891 patients. J Bone Joint Surg Am. 1991;73(10):1507-1525.
47.
KauxJFForthommeBGoffCLCrielaardJMCroisierJL. Current opinions on tendinopathy. J Sports Sci Med. 2011;10(2):238-253.
KraushaarBSNirschlRP. Tendinosis of the elbow (tennis elbow). Clinical features and findings of histological, immunohistochemical, and electron microscopy studies. J Bone Joint Surg Am. 1999;81(2):259-278.
50.
LaPradeCMJamesEWLaPradeRFEngebretsenL. How should we evaluate outcomes for use of biologics in the knee?J Knee Surg. 2015;28(1):35-44.
LiCYWuXYTongJB. Comparative analysis of human mesenchymal stem cells from bone marrow and adipose tissue under xeno-free conditions for cell therapy. Stem Cell Res Ther. 2015;6:55.
53.
LianOScottAEngebretsenLBahrRDuronioVKhanK. Excessive apoptosis in patellar tendinopathy in athletes. Am J Sports Med. 2007;35(4):605-611.
54.
MaffulliNKhanKMPudduG. Overuse tendon conditions: time to change a confusing terminology. Arthroscopy. 1998;14(8):840-843.
55.
MaffulliNLongoUGDenaroV. Novel approaches for the management of tendinopathy. J Bone Joint Surg Am. 2010;92(15):2604-2613.
56.
MaffulliNWongJAlmekindersLC. Types and epidemiology of tendinopathy. Clin Sports Med. 2003;22(4):675-692.
57.
MalliarasPCookJ. Changes in anteroposterior patellar tendon diameter support a continuum of pathological changes. Br J Sports Med. 2011;45(13):1048-1051.
58.
MalliarasPPurdamCMaffulliNCookJ. Temporal sequence of greyscale ultrasound changes and their relationship with neovascularity and pain in the patellar tendon. Br J Sports Med. 2010;44(13):944-947.
59.
MarxRECarlsonEREichstaedtRMSchimmeleSRStraussJEGeorgeffKR. Platelet-rich plasma: growth factor enhancement for bone grafts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1998;85(6):638-646.
60.
MatsumotoTInghamSMMifuneY. Isolation and characterization of human anterior cruciate ligament-derived vascular stem cells. Stem Cells Dev. 2012;21(6):859-872.
61.
MazzoccaADMcCarthyMBChowaniecDM. Platelet-rich plasma differs according to preparation method and human variability. J Bone Joint Surg Am. 2012;94(4):308-316.
62.
McCreeshKLewisJ. Continuum model of tendon pathology - where are we now?Int J Exp Pathol. 2013;94(4):242-247.
63.
MiddletonKKBarroVMullerBTeradaSFuFH. Evaluation of the effects of platelet-rich plasma (PRP) therapy involved in the healing of sports-related soft tissue injuries. Iowa Orthop J. 2012;32:150-163.
64.
MifuneYMatsumotoTTakayamaK. Tendon graft revitalization using adult anterior cruciate ligament (ACL)-derived CD34+ cell sheets for ACL reconstruction. Biomaterials. 2013;34(22):5476-5487.
65.
MillarNLHueberAJReillyJH. Inflammation is present in early human tendinopathy. Am J Sports Med. 2010;38(10):2085-2091.
66.
MishraAHarmonKWoodallJVieiraA. Sports medicine applications of platelet rich plasma. Curr Pharm Biotechnol. 2012;13(7):1185-1195.
67.
MishraAKSkrepnikNVEdwardsSG. Efficacy of platelet-rich plasma for chronic tennis elbow: a double-blind, prospective, multicenter, randomized controlled trial of 230 patients. Am J Sports Med. 2014;42(2):463-471.
68.
MolloyTWangYMurrellG. The roles of growth factors in tendon and ligament healing. Sports Med. 2003;33(5):381-394.
69.
MoranCJPascual-GarridoCChubinskayaS. Restoration of articular cartilage. J Bone Joint Surg Am. 2014;96(4):336-344.
70.
MosnaFSensebeLKramperaM. Human bone marrow and adipose tissue mesenchymal stem cells: a user’s guide. Stem Cells Dev. 2010;19(10):1449-1470.
71.
MurawskiCDvan EckCFIrrgangJJTashmanSFuFH. Operative treatment of primary anterior cruciate ligament rupture in adults. J Bone Joint Surg Am. 2014;96(8):685-694.
72.
MurrayIRCorselliMPetriglianoFASooCPeaultB. Recent insights into the identity of mesenchymal stem cells: implications for orthopaedic applications. Bone Joint J. 2014;96(3):291-298.
73.
MurrayIRPeaultB. Q&A: Mesenchymal stem cells - where do they come from and is it important?BMC Biol. 2015;13(1):99.
74.
MurrayIRWestCCHardyWR. Natural history of mesenchymal stem cells, from vessel walls to culture vessels. Cell Mol Life Sci. 2014;71(8):1353-1374.
75.
MurrayMMFlemingBC. Use of a bioactive scaffold to stimulate anterior cruciate ligament healing also minimizes posttraumatic osteoarthritis after surgery. Am J Sports Med. 2013;41(8):1762-1770.
OhJHKimWParkKURohYH. Comparison of the cellular composition and cytokine-release kinetics of various platelet-rich plasma preparations. Am J Sports Med. 2015;43(12):3062-3070.
78.
ParkJSYangHJWooDGYangHNNaKParkKH. Chondrogenic differentiation of mesenchymal stem cells embedded in a scaffold by long-term release of TGF-beta 3 complexed with chondroitin sulfate. J Biomed Mater Res A. 2010;92(2):806-816.
79.
Pascual-GarridoCRolonAMakinoA. Treatment of chronic patellar tendinopathy with autologous bone marrow stem cells: a 5-year-followup. Stem Cells Int. 2012;2012:953510.
80.
PingelJLuYStarborgT. 3-D ultrastructure and collagen composition of healthy and overloaded human tendon: evidence of tenocyte and matrix buckling. J Anat. 2014;224(5):548-555.
81.
RadiceFYanezRGutierrezVRosalesJPinedoMCodaS. Comparison of magnetic resonance imaging findings in anterior cruciate ligament grafts with and without autologous platelet-derived growth factors. Arthroscopy. 2010;26(1):50-57.
82.
RandelliPConfortiEPiccoliM. Isolation and characterization of 2 new human rotator cuff and long head of biceps tendon cells possessing stem cell-like self-renewal and multipotential differentiation capacity. Am J Sports Med. 2013;41(7):1653-1664.
83.
RaposioECaruanaGBonominiSLibondiG. A novel and effective strategy for the isolation of adipose-derived stem cells: minimally manipulated adipose-derived stem cells for more rapid and safe stem cell therapy. Plast Reconstr Surg. 2014;133(6):1406-1409.
84.
RibohJCSaltzmanBMYankeABFortierLColeBJ. Effect of leukocyte concentration on the efficacy of platelet-rich plasma in the treatment of knee osteoarthritis [published online ahead of print April29, 2015]. Am J Sports Med. DOI: 10.1177/0363546515580787.
85.
RichardsonSMCurranJMChenR. The differentiation of bone marrow mesenchymal stem cells into chondrocyte-like cells on poly-L-lactic acid (PLLA) scaffolds. Biomaterials. 2006;27(22): 4069-4078.
86.
RodriguezTMSaldiasAIrigoMZamoraJVPeroneMJDeweyRA. Effect of TGF-beta1 stimulation on the secretome of human adipose-derived mesenchymal stromal cells. Stem Cells Transl Med. 2015;4(8):894-898.
87.
RoslandGVSvendsenATorsvikA. Long-term cultures of bone marrow-derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation. Cancer Res. 2009;69(13):5331-5339.
88.
SharmaPMaffulliN. Tendon injury and tendinopathy: healing and repair. J Bone Joint Surg Am. 2005;87(1):187-202.
89.
SmithRKKordaMBlunnGWGoodshipAE. Isolation and implantation of autologous equine mesenchymal stem cells from bone marrow into the superficial digital flexor tendon as a potential novel treatment. Equine Vet J. 2003;35(1):99-102.
90.
SmithRKWerlingNJDakinSGAlamRGoodshipAEDudhiaJ. Beneficial effects of autologous bone marrow-derived mesenchymal stem cells in naturally occurring tendinopathy. PLoS One. 2013;8(9):e75697.
91.
TakayamaKKawakamiYMifuneY. The effect of blocking angiogenesis on anterior cruciate ligament healing following stem cell transplantation. Biomaterials. 2015;60:9-19.
92.
ThomopoulosSParksWCRifkinDBDerwinKA. Mechanisms of tendon injury and repair. J Orthop Res. 2015;33(6):832-839.
93.
VavkenPFlemingBCMastrangeloANMachanJTMurrayMM. Biomechanical outcomes after bioenhanced anterior cruciate ligament repair and anterior cruciate ligament reconstruction are equal in a porcine model. Arthroscopy. 2012;28(5):672-680.
94.
VavkenPSadoghiPMurrayMM. The effect of platelet concentrates on graft maturation and graft-bone interface healing in anterior cruciate ligament reconstruction in human patients: a systematic review of controlled trials. Arthroscopy. 2011;27(11):1573-1583.
95.
WeiXMaoZHouY. Local administration of TGFbeta-1/VEGF165 gene-transduced bone mesenchymal stem cells for Achilles allograft replacement of the anterior cruciate ligament in rabbits. Biochem Biophys Res Commun. 2011;406(2):204-210.
96.
WeibrichGHansenTKleisWBuchRHitzlerWE. Effect of platelet concentration in platelet-rich plasma on peri-implant bone regeneration. Bone. 2004;34(4):665-671.
97.
YamazakiSYasudaKTomitaFTohyamaHMinamiA. The effect of transforming growth factor-beta1 on intraosseous healing of flexor tendon autograft replacement of anterior cruciate ligament in dogs. Arthroscopy. 2005;21(9):1034-1041.
98.
YasudaKTomitaFYamazakiSMinamiATohyamaH. The effect of growth factors on biomechanical properties of the bone-patellar tendon-bone graft after anterior cruciate ligament reconstruction: a canine model study. Am J Sports Med. 2004;32(4):870-880.
99.
YoshidaRChengMMurrayMM. Increasing platelet concentration in platelet-rich plasma inhibits anterior cruciate ligament cell function in three-dimensional culture. J Orthop Res. 2014;32(2):291-295.
100.
YoungM. Stem cell applications in tendon disorders: a clinical perspective. Stem Cells Int. 2012;2012:637836.
101.
ZhangJMiddletonKKFuFHImHJWangJH. HGF mediates the anti-inflammatory effects of PRP on injured tendons. PLoS One. 2013;8(6):e67303.
102.
ZhangJWangJH. Platelet-rich plasma releasate promotes differentiation of tendon stem cells into active tenocytes. Am J Sports Med. 2010;38(12):2477-2486.
103.
ZukPAZhuMMizunoH. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001;7(2):211-228.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
