Treatment of Knee Meniscus Pathology: Rehabilitation, Surgery, and Orthobiologics

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PM R XXX (2018) 1-17
6 www.pmrjournal.org 86
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8 Narrative Review 88
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Treatment of Knee Meniscus Pathology: 91
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Rehabilitation, Surgery, and Orthobiologics 93
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Paul S. Chirichella, MD, Steven Jow, MD, Stephen Iacono, MD, 97
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19 Hannah E. Wey, MD, Gerard A. Malanga, MD 99
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25 Abstract 105
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27 The meniscal tear treatment paradigm traditionally begins with conservative measures such as physical therapy with referral 107
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for operative management for persistent or mechanical symptoms. As a result, the partial meniscectomy is performed more than 109
30 any other orthopedic procedure in the United States. This treatment paradigm has shifted because the recent literature has 110
31 supported the attempt to preserve or repair the meniscus whenever possible given its importance for the structural integrity of 111
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the knee joint and the risk of early osteoarthritis associated after meniscus excision. Choosing an appropriate management
33 113
34 strategy depends on multiple factors such as patient demographics and location of the tear. Physical therapy remains a first-line 114
35 treatment for knee pain secondary to meniscus tear and should be pursued in the setting of acute and chronic knee pain. 115
36 Furthermore, there is a growing amount of evidence showing that elderly patients with complex meniscus tears in the setting of 116
37 117
38 degenerative arthritis should not undergo arthroscopic surgery. Direct meniscus repair remains an option in ideal patients who are 118
39 young, healthy, and have tears near the more vascular periphery of the meniscus but it is not suitable for all patients. Use of 119
40 orthobiologics such as platelet-rich plasma and mesenchymal stem cells have shown promise in augmenting surgical repairs or as 120
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standalone treatments, although research for their use in meniscal tear management is limited. 122
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48 Introduction 5.1 per 100 000 athlete exposures in high school-age 128
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athletes [7]. 130
51 The menisci are fibrocartilaginous structures that Considering the vital importance of the menisci to 131
52 contribute to static weight bearing, distributing normal knee function, treatment paradigms have 132
53 133
54 compressive forces during joint movement, joint evolved greatly from when they were perceived to be 134
55 lubrication, joint stabilization, and proprioception inconsequential and functionless structures [10]. It 135
56 136
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[1-3]. Meniscal tears are a commonly occurring muscu- was not until 1977 that the partial meniscectomy 137
58 loskeletal injury across all age and functional groups began to be recognized as superior to total menis- 138
59 [4-7], with incidental radiographic pathologic changes cectomy surgery [11]. More recently, the paradigm has 139
60 140
61 occurring in the asymptomatic population [8]. The mean further evolved with the knowledge that partial 141
62 annual incidence has been estimated to be as high as 60- meniscectomy has no greater benefit than conserva- 142
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64 70 per 100 000 knee injuries based on previous reviews tive management of degenerative meniscal tears [12]. 144
65 [9]. The rate is higher in those older than 40 years and in Conservative management continues to be a mainstay 145
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men vs women [4] and in the medial meniscus compared of treatment after knee injuries and meniscal repair 147
68 with the lateral meniscus [5]. The incidence also has techniques continue to evolve to preserve meniscal 148
69 been found to be higher in active populations such as tissue whenever possible. There also has been growing 149
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71 military members, in whom the meniscus tear incidence interest in the use of orthobiologics, such as platelet- 151
72 rate was determined to be 8.27 per 1000 person-years rich plasma (PRP) and mesenchymal stem cells (MSCs), 152
73 153
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(10 times higher than any documented civilian study) to enhance the potential healing effects of articular 154
75 [6]. Acute meniscal tears also occur at higher fre- and meniscal tissue. Recognizing differences in pre- 155
76 quencies during athletic events, reportedly as high as sentation is integral to choosing the optimal treatment 156
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79 1934-1482/$ - see front matter ª 2018 by the American Academy of Physical Medicine and Rehabilitation 159
80 https://doi.org/10.1016/j.pmrj.2018.08.384 160
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2 Treatment of Knee Meniscus Pathology Q1
161 strategy. In this article, we review meniscus anatomy, 241

162 242
163 classification of meniscal tears, meniscal healing po- 243
164 tential, and clinical presentation and provide an 244
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updated review of current and evolving treatment 246
167 options for meniscal tears. 247
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169 249
170 Anatomy of Knee Menisci 250
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172 252
173
The knee menisci are crescent-shaped wedges of 253
174 fibrocartilage situated between the femoral condyles 254
175 Q2 and the tibial plateaus [13,14] (Figure 1). The outer 255
176 256
177 edges of the menisci are convex with attachments to 257
178 the joint capsule and the inner edges taper to a concave 258
179 259
180 free edge [15]. The medial meniscus is C-shaped and 260
Figure 1. Drawing of the tibial plateau showing the shape and at-
181 covers approximately 60% of the medial compartment. tachments of the medial and lateral menisci. Reproduced, with 261
182 262
183
The posterior horn of the medial meniscus has a firm permission of Elsevier, from Caldwell GL, Allen AA, Fu FH. Functional 263
184 attachment to the intercondylar area of the tibia near anatomy and biomechanics of the meniscus. Oper Tech Sports Med 264
185 the posterior cruciate ligament and the anterior horn 1994;2:152-163 [14]. 265
186 266
187 inserts into the anterior intercondylar area with fibers 267
188 intermingling with the anterior cruciate ligament (ACL) identified 3 distinguishable cell types that included 268
189 269
190
[16,17] and the transverse ligament in 64% of dissections elongated fibroblast-like cells, polygonal cells, and 270
191 [16]. In addition to its capsular attachment, the medial small round chondrocyte-like cells. The outer portion of 271
192 meniscus shares fibers with the medial collateral liga- 272
193 the meniscus has been shown in histologic studies to 273
194 ment [18]. The lateral meniscus is more circular than contain a larger proportion of fibroblast-like cells, 274
195 the medial meniscus and has been reported to cover as 275
196
whereas the inner avascular portion of the meniscus 276
197
much as 80% of the lateral compartment surface. The contains more rounded cells that behave similar to 277
198 anterior horn inserts into the anterior intercondylar chondrocytes such as in the articular cartilage [29,30] 278
199 area with its fibers also blending with the ACL. The 279
200 (Figure 3). The extracellular matrix surrounding the 280
201 posterior horn has a more variable insertion but will fibroblast-like cells in the outer portion of the meniscus 281
202 typically insert anterior to the posterior horn of the 282
203 contains mostly type I cartilage in contrast to the inner 283
204 medial meniscus through the ligament of Wrisberg, portion of the meniscus, which is mostly composed of 284
205 the ligament of Humphry, and from fascia covering the type II collagen and aggrecan in an extracellular matrix 285
206 286
207
popliteus muscle [13,16,19]. similar to the hyaline cartilage composition [31]. The 287
208 The menisci are composed primarily of water (72%) third cell type, found in the superficial zone of the 288
209 with the remaining 28% primarily composed of colla- 289
210 meniscus, has an intermediate morphology between 290
211 gens, glycosaminoglycans, DNA, and glycoproteins fibrochondrocyte and fibroblast [29] and it has been 291
212 [20,21]. The proportion of these components is postulated that these cells might have progenitor 292
213 293
214
dependent on multiple factors, including age, in- properties that initiate wound healing [32]. 294
215 juries, and pathology [21,22]. The collagen is pre- 295
216 dominantly type I, with small quantities of types II, III, 296
217 297
218 and V [23]. The peripheral and deep arrangement of 298
219 collagen is primarily circumferential, with radially 299
220 300
221
arranged fibers being more common medially and su- 301
222 perficially [19,24] (Figure 2). This arrangement is 302
223 important in counteracting the compressive forces 303
224 304
225 exerted by the tibia and femur, which are radially 305
226 directed by converting them to traction forces and 306
227 307
228 transmitting the forces circumferentially to their 308
229 strong anterior and posterior horn attachments in the 309
230 310
231
tibia by “hoop strain” [24-26]. Proteoglycans are hy- 311
232 drophilic molecules that contribute to the large water 312
233 content and shock absorption properties of the 313
234 314
235 meniscus through the time-dependent exudation of 315
Figure 2. Synoptic drawing showing 3 distinct layers of the meniscus by
236 water from the extracellular matrix [21,23,27]. 316
237 scanning electron microscopy: (1) superficial network, (2) lamellar 317
238
In the mature meniscus, the morphologic type of cells layer, and (3) central main layer. Reproduced, with permission of 318
239 present varies based on location, with no uniform clas- Elsevier, from Petersen W, Tillmann B. Collagenous fibril texture of the 319
240 sification accepted in the literature. Nakata et al [28] human knee joint menisci. Anat Embryol (Berl) 1998;197:317-324 [24]. 320

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343 Figure 3. (Left) Regional variations in vascularization showing the red-red region, white-red region, and white-white region. (Right) Variations in 423
344 cell phenotypes in the meniscus relative to vascularity. Reproduced, with permission of Elsevier, from Makris EA, Hadidi P, Athanasiou KA. The knee 424
345 meniscus: structure-function, pathophysiology, current repair techniques, and prospects for regeneration. Biomaterials 2011;32:7411-7431 [30]. 425
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The main vascular supply to the menisci originates Clinical Presentation, Classification, and Healing 430
351 from the inferior and superior medial and lateral Potential 431
352 geniculate vessels arising from the popliteal artery. 432
353 433
354 These vessels form a peri-meniscal capillary plexus Acute meniscal tears often present with recognizable 434
355 within the synovial and capsular tissue that supplies symptoms after a twisting knee injury. Most acute tears 435
356 436
357
the peripheral border of the meniscus (Figure 4). The occur during sporting events [35], with cutting and 437
358 peripheral 10%-30% of the medial meniscus border and pivoting sports requiring knee flexion at high activity 438
359 10%-25% of the lateral meniscus border are well vas- levels generating the highest risk for meniscal injury 439
360 440
361 cularized, with the remainder of the meniscus [36]. Patients will often report a twisting knee injury 441
362 receiving nourishment from synovial fluid [19,33,34]. with an associated snapping sound followed by sharp 442
363 443
364 This has led to meniscus zones being described in a localized pain. They also might report delayed knee 444
365 radial direction as red-red, red-white, and white- swelling and exacerbation of pain on deep knee bending 445
366 446
367
white based on vascularity. and twisting. Mechanical locking of the knee can occur 447
368 in the setting of flap or bucket-handleetype tears [35]. 448
369 In the chronic setting, patients might complain of knee 449
370 450
371 pain associated with intermittent swelling and me- 451
372 chanical symptoms [35]. Risk factors for nontraumatic, 452
373 453
374
degenerative meniscal injury include age older than 60 454
375 years, male gender, and work-related kneeling, squat- 455
376 ting, or climbing [37]. 456
377 457
378 There have been many proposed classification sys- 458
379 tems to describe meniscal tears without an established 459
380 460
381
standard. However, meniscal tears are generally classi- 461
382 fied by pattern, location, and thickness as determined 462
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383 at magnetic resonance imaging (MRI) or arthroscopy 463

384 464
385 [38,39] (Figure 5). Tear types include vertical (longitu- 465
386 dinal or radial), horizontal, and complex [9,19,40,41]. 466
387 467
388 Vertical longitudinal tears result in disruption of the 468
389 superficial radial collagen fibers in line with the 469
390 Figure 4. Frontal section of the medial compartment of the knee 470
391 displaying branching radial vessels from the peri-meniscal capillary circumferential fibers. When large, the inner meniscus 471
392 plexus (PCP), femur (F), and tibia (T). Also labeled are the (1) red-red can displace into the intercondylar notch, resulting in a 472
393 (RR), (2) red-white (RW), and (3) white-white (WW) zones. Repro- commonly described “bucket-handle” tear [19,41]. 473
394 474
duced, with permission of Elsevier, from Miller RH, Azar FM. Knee Longitudinal tears also are more commonly associated
395 475
injuries. In: Azar FM, Canale ST, Beaty JH, Campbell WC, eds. Camp-
396 with trauma [42] and typically occur in the red-white 476
397 bell’s Operative Orthopaedics. 13th ed. Philadelphia, PA: Elsevier, 477
398 2017, 2121-2297 [19]. Originally from Arnoczky SP, Warren RF, Spivak and white-white zones of the meniscus [43]. Horizon- 478
399 JM. Meniscal repair using an exogenous fibrin clot. An experimental tal tears involve separation of the meniscus into 2 layers 479
400 study in dogs. J Bone Joint Surg Am 1988;70:1209-1217 [33]. while leaving circumferential fibers intact and are 480

4 Treatment of Knee Meniscus Pathology
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531 Figure 5. Illustration of proposed arthroscopic meniscal tear classification system by the International Society of Arthroscopy, Knee Surgery and 611
532 Orthopaedic Sports Medicine Knee Committee. Reproduced, with permission of Elsevier, from Wadhwa V, Omar H, Coyner K, Khazzam M, Robertson 612
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W, Chhabra A. ISAKOS classification of meniscal tearsdIllustration on 2D and 3D isotropic spin echo MR imaging. Eur J Radiol 2016;85:15-24 [39].
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536 frequently asymptomatic. Radial tears occur more healing response has been noted when the tear site is 616
537 617
commonly in the lateral meniscus compared with the within the inner two-thirds of meniscal tissue, outside
538 618
539 medial meniscus and involve circumferential fibers with the red-red zone [55]. 619
540 consequent disruption of hoop stresses. When oblique in Pathologic studies have shown that migration of peri- 620
541 621
542 pattern, radial tears can result in flaps that might cause meniscal tissue and synovial cells over the surface of the 622
543 mechanical symptoms [19]. Complex, or degenerative, meniscus to the tear site is vital in the healing response 623
544 624
545
tears typically involve multiple tear configurations [44] within the vascular zone [51,53,56]. However, this 625
546 and are the most common meniscal lesion, with peak spontaneous healing response fails in the avascular 626
547 incidence at 41-50 years of age in men and 61-70 years portion of the meniscus [57-59], indicating that those 627
548 628
549 of age in women [9]. Degenerative and radial tear types cells are intrinsically incapable of mounting a sufficient 629
550 also are associated with a significantly higher rate of repair response [33]. Mesiha et al [8] found that in pa- 630
551 631
552
articular cartilage change compared with longitudinal tients older than 40 years, there were lower intrinsic 632
553 tears [8,45,46]. cellularity in the meniscus and decreased peri-meniscal 633
554 The success of meniscal healing can vary based on the response after a tear, which would likely contribute to 634
555 635
556 patient’s age, length of time since injury, and tear type the poor healing response seen in other clinical studies. 636
557 [47-50]. It has been well established that peripheral Notably, they also found that there was no proliferative 637
558 638
559 meniscal tears can successfully heal spontaneously or fibroblastic or angiogenic response to injury of the 639
560 after intervention [47,51-54], although a poor intrinsic meniscus. Compared with other soft tissue healing, 640

641 meniscal tears also lack a fibrin clot or bridging struc- swelling, delayed onset of symptoms after injury, and 721
642 722
643 ture to stabilize the tear site owing to the presence of minimally restricted range of motion [68]. 723
644 fibrinolytic enzymes in synovial fluid [60]. Detailed therapeutic regimens designed for nonop- 724
645 725
646
Another challenge to effective meniscal healing is the erative management of meniscal tears have not been 726
647 inflammatory environment present in the synovial fluid in well studied in the literature, with a noted lack of 727
648 the setting of acute or chronic meniscal tears [61,62]. randomized controlled trials comparing physical therapy 728
649 729
650 Interleukin (IL)-1b and tumor necrosis factor-a are with time and rest. However, there is an abundance of 730
651 generally acknowledged as primary inflammatory medi- literature validating the success of strengthening and 731
652 732
653
ators associated with cartilage degeneration, bone aerobic conditioning programs in managing knee pain 733
654 changes, and synovial inflammation in the setting of and improving general function in the setting of knee 734
655 osteoarthritis [63] and their presence has suppressed osteoarthritis [69,70]. Stensrud et al [71] developed a 735
656 736
657 meniscal repair in vitro [64]. Increased levels of proin- 12-week strength training and neuromuscular rehabili- 737
658 flammatory cytokines IL-6, IL-8, and tumor necrosis fac- tation regimen for managing knee pain with concurrent 738
659 739
660 tor-a also have been shown to persist 3 months after MRI-diagnosed degenerative meniscal tears that was 740
661 meniscal tear [62], and increase of IL-6 and tumor ne- extrapolated from programs successfully used to 741
662 742
663
crosis factor-a 18 years after meniscectomy correlates manage knee osteoarthritis. This neuromuscular 743
664 with radiographic progression of osteoarthritis [61]. regimen aimed to improve the position of the trunk and 744
665 Furthermore, the presence of degradative enzymes such lower limbs relative to one another and incorporate 745
666 746
667 as metalloproteinases and aggrecanases can contribute dynamic lower extremity strengthening through the use 747
668 to meniscal degradation through proteoglycan and of single-leg exercises on varying surfaces and plyo- 748
669 749
670
collagen degradation [65]. Modifying this proin- metrics. In a series of 20 patients, they documented 750
671 flammatory environment in the synovial fluid can mitigate clinically meaningful improvement in Knee Injury and 751
672 the inhibitory effects of proinflammatory cytokines [66]. Osteoarthritis Outcome Score (KOOS) quality-of-life and 752
673 753
674 Despite these challenges, studies have shown that pain subscales in 16 patients and improved measurable 754
675 various anabolic growth factors, such as transforming quadriceps strength in all patients at the end of the 755
676 756
677
growth factor-b, insulin-like growth factor-1, fibroblast program. Results were sustained or improved at 1 year 757
678 growth factor, and vascular endothelial growth factor, and no patients underwent surgery [71]. Similar results 758
679 can benefit angiogenesis, chondrogenesis, and cell sur- were seen in conservative management groups of 4 759
680 760
681 vival in the setting of meniscal tears [67]. The induction randomized controlled trials [72-75] comparing arthro- 761
682 of these growth factors in regenerative meniscal repair scopic partial meniscectomy (APM) with physical ther- 762
683 763
684 techniques continues to be a promising focus of ongoing apy or an exercise program for management of knee 764
685 research. pain secondary to meniscal tears (Table 1). In all 4 765
686 766
studies, patients met minimum clinically important
687 767
688 changes in reported outcomes at short-term and long- 768
689 Rehabilitation and Conservative Management term follow-up but such changes were less apparent 769
690 770
691 when only a home exercise program was used [72]. 771
692 Initial nonoperative management of meniscal tears is Furthermore, physical therapy has been shown to 772
693 773
694
dependent on clinical presentation and is typically improve hamstring strength and quadriceps endurance 774
695 reserved for patients who do not have severely parameters after partial meniscectomy [76]. 775
696 restricted range of motion, locking, or instability of the 776
697 777
698 afflicted knee. Those deemed good candidates for APMdSuperior to Conservative Management in the 778
699 conservative management after an acute knee injury Degenerative Meniscal Tear? 779
700 780
701
should be initially managed with rest, ice, compression, 781
702 and elevation of the injured knee. Offloading also might The surgical treatment of meniscal tears is often 782
703 be required for comfort, although patients can progress recommended to patients with mechanical symptoms, 783
704 784
705 to full weight bearing when tolerated [35]. Thereafter, such as catching and locking, or to treat symptoms of 785
706 physical therapy can aid in a gradual resolution of pain if conservative management fails. The most 786
707 787
708 symptoms over 6 weeks [11]. A therapeutic program frequently used treatment is APM. APM is the most 788
709 should focus early on controlling and managing swelling common orthopedic procedure, with more than 700 000 789
710 790
711
while maintaining knee range of motion. The program cases annually in the United States and estimated direct 791
712 should later incorporate quadriceps and hamstring medical costs over $4 billion per year [77,78]. Ran- 792
713 strengthening, eventually progressing to dynamic pro- domized control studies have shown that APM and 793
714 794
715 prioceptive training. Conditioning can be maintained physical therapy after meniscal tears result in signifi- 795
716 with use of an exercise bike and walking and eventually cant functional improvement and decreased pain 796
717 797
718
progress to running and other sport-specific exercises compared with baseline; however, no randomized trial 798
719 [68]. Factors that can favor success with conservative effectively supports the notion APM is superior to 799
720 treatment include ability to bear weight, minimal nonsurgical management of degenerative meniscal tears 800

801 Table 1 881

802 Outcomes in conservative management groups in randomized controlled trials evaluating the efficacy of arthroscopic partial meniscectomy 882
803 883
804 Control Group Minimum 884
805 Patients, n; Clinically 885
806 Study Study Type Intervention Outcome Measures Subscale Change from Baseline Important Change 886
807 887
808 Katz et al multicenter 169; physical WOMAC-pf 18.5 (15.6-21.5), 22.8 8 [14] 888
809 2013 [73] RCT therapy then (19.8-25.8) 889
810 exercise program 890
811 891
812
KOOS pain (6 and 12 mo) 21.3 (18.4-24.2), 27.3 8-10 [30] 892
813 (24.1-30.4) 893
814 Yim et al single-center 52; physical therapy Lysholm Knee Scoring 15.2, 17.1, 18.9, 19.1 10 [75] 894
815 2013 [75] RCT then exercise Scale 895
816 program 896
817 897
VAS (3, 6, 12, and 24 mo) 2.2, 2.8, 3.1, 1.99 [14]
818 898
819 3.2 899
820 Gauffin et al Single-center 75; home exercise KOOS† (3 and 12 mo) pain 12.9 (8.0-17.7), 16.6 8-10 [30] 900
821 2014 [72] RCT program only; *68 (10.6-22.6) 901
822 after crossover 902
823 symptoms 9.5 (5.4-13.7), 15.0 8-10 [30] 903
824 904
(9.8-20.0)
825 905
826 activity of daily 8.5 (4.3-12.7), 11.7 8-10 [30] 906
827 living (6.5-16.9) 907
828 sports and 14.5 (8.5-20.6), 21.1 8-10 [30] 908
829 recreation (13.4-28.8) 909
830 quality of life 12.9 (7.4-18.5), 21.9 8-10 [30] 910
831 911
832
(15.4-28.4) 912
833 Kise et al multicenter 70; physical KOOS₄ (12 mo) 25.3 (21.6-29.0) 8-10 [30] 913
834 2016 [74] RCT therapy, then 914
835 exercise program 915
836 916
837 RCT ¼ randomized controlled trial; WOMAC-pf ¼ Western Ontario and McMaster Universities Osteoarthritis Index with physical function subscale 917
838 score; KOOS ¼ Knee Injury and Osteoarthritis Outcome Score; VAS ¼ visual analog scale; KOOS₄ ¼ aggregated Knee Injury and Osteoarthritis 918
839 Outcome Score omitting activity of daily living subscale. 919
840 * ---. Q9 920
841 † 921
Results from “as treated” analysis.
842 922
843 923
844 924
845 (Table 2). Moreover, a clinical practice guideline score (23.1 points in partial meniscectomy group vs 26.3 925
846 recently published in the British Journal of Medicine points in sham surgery group) and the WOMET score 926
847 927
848 strongly recommends “against the use of arthroscopy in (27.3 in partial meniscectomy group vs 31.6 in sham 928
849 nearly all patients with degenerative knee disease” and surgery group) and continued to show a statistically 929
850 930
851 even recommends “using number of arthroscopies per- insignificant difference. The investigators concluded 931
852 formed in patients with degenerative knee disease as an that the results supported the notion that APM provided 932
853 933
854
indicator of quality care” [12]. Nevertheless, APM is no significant benefit over placebo surgeries in patients 934
855 frequently used in middle-aged and older patients with degenerative meniscal tear and no knee osteoar- 935
856 [79,80] who might have concomitant degenerative thritis [83]. 936
857 937
858 changes in the menisci and/or osteoarthritis [81]. The Meniscal Repair in Osteoarthritis Research 938
859 The Finnish Degenerative Meniscal Lesion Study (FI- (METEOR) trial was a large multicenter randomized 939
860 940
861
DELITY) trial was a double-blinded, sham-controlled control trial involving 351 patients older than 45 years 941
862 trial involving 146 patients 35-65 years old with non- with degenerative meniscus tears and evidence of mild 942
863 traumatic degenerative meniscal tears and no evidence to moderate osteoarthritis and compared the results of 943
864 944
865 of osteoarthritis. In this study, the mean improvement partial meniscectomy plus postoperative physical ther- 945
866 at 12 months was measured by the Lysholm Knee Scoring apy with standardized physical therapy regimen alone 946
867 947
868
Scale (LKSS) score (21.7 points in partial meniscectomy using the Western Ontario and McMaster Universities 948
869 group vs 23.3 points in sham surgery group) and the Osteoarthritis Index (WOMAC) physical function score. 949
870 Western Ontario Meniscal Evaluation Tool (WOMET) At 6 months, patients who underwent partial menis- 950
871 951
872 score (24.6 in partial meniscectomy group vs 27.1 in cectomy had a WOMAC score improvement of 20.9 952
873 sham surgery group), which showed no significant dif- points compared with 18.5-point improvement in the 953
874 954
875 ference in improvements in patients undergoing partial conservative treatment group. Comparing the operative 955
876 meniscectomy compared with sham surgery despite with the nonoperative treatment showed the results 956
877 957
878
adequate power [82]. Furthermore, a 2-year follow-up were not significant. Similarly, the comparison between 958
879 study was recently published showing that the mean the 2 groups at 12 months was not significant. Also noted 959
880 improvement at 24 months was measured by the LKSS was that 30% of patients in the physical therapy group 960

961 Table 2 1041

962 Recent randomized controlled trials evaluating the efficacy of arthroscopic partial meniscectomy 1042
963 1043
964 Treatment 1044
965 Control Group Group 1045
966 Osteoarthritis Patients, n; Patients, n; 1046
967 1047
Study Study Type Blinding Grading Intervention Intervention Outcome Measures Results
968 1048
969 Herrlin et al single-center none Ahlback 49; exercise 47; APM and
KOOS at 60 mo, no statistically 1049
970 2013 [88] RCT criteria program exercise Lysholm Knee significant difference 1050
971 1051
972
grade 0-1 Scoring Scale, between groups 1052
973 Tegner Activity 1053
974 Scale, VAS scores at 1054
975 24 and 60 mo 1055
976 Katz et al 2013 multicenter none Kellgren- 169; physical 161; APM WOMAC-pf, KOOS no statistically 1056
977 1057
[73] RCT Lawrence therapy then pain score, SF-36 significant difference
978 1058
979 grade 0-3 exercise program physical activity between groups 1059
980 scores at 6 and 12 1060
981 mo 1061
982 Sihovenen et al multicenter participant Kellgren- 76; sham 70; APM Lysholm Knee Scoring no statistically 1062
983 2013 [82] RCT and assessor Lawrence arthroscopic Scale, WOMET, VAS significant difference 1063
984 1064
grade 0-1 surgery at 12 mo between groups
985 1065
986 Yim et al 2013 single-center none Kellgren- 52; physical 50; APM Lysholm Knee Scoring no statistically 1066
987 [75] RCT Lawrence therapy, then Scale, VAS, patient significant difference 1067
988 grade 0-1 exercise program satisfaction, between groups 1068
989 Tegner Activity 1069
990 Scale scores at 3, 6, 1070
991 1071
992
12, and 24 mo 1072
993 Gauffin et al single-center none Ahlback 75; exercise 75; APM; *82 KOOS, EQ5D (includes significant intention- 1073
994 2014 [72] RCT criteria program; *68 after VAS), PAS, to-treat difference in 1074
995 grade 0, after crossover crossover symptom KOOS Pain score at 3 1075
996 Kellgren- satisfaction at 3 mo (11.6, 4.7-18.5, 1076
997 1077
Lawrence and 12 mo P ¼ .001) and 12 mo
998 1078
999 grade 0-2 (10.6, 3.4-17.7, P ¼ 1079
1000 (93% 0-1) .004); other results 1080
1001 showed no 1081
1002 statistically 1082
1003 significant difference 1083
1004 1084
Kise et al 2016 multicenter assessor only Kellgren- 70; exercise 70; APM KOOS, SF-36 physical, significant increase in
1005 1085
1006 [74] RCT Lawrence program mental, and thigh strength in 1086
1007 grade 0-3 performance tests, exercise group at 3 1087
1008 lower extremity mo; other results 1088
1009 strength at 3, 6, showed no 1089
1010 and 12 mo statistically 1090
1011 1091
1012
significant difference 1092
1013 RCT ¼ randomized controlled trial; APM ¼ arthroscopic partial meniscectomy; KOOS ¼ Knee Injury and Osteoarthritis Outcome Score; VAS ¼ visual 1093
1014 1094
analog scale; WOMAC-pf ¼ Western Ontario and McMaster Universities Osteoarthritis Index physical function subscale score; SF-36 ¼ Medical
1015 1095
1016 Outcomes Study 36-Item Short-Form Health Survey; WOMET ¼ Western Ontario Meniscal Evaluation Tool; EQ5D ¼ EuroQol Quality of Life Measure; 1096
1017 PAS ¼ Physical Activity Scale. 1097
1018 * ---. 1098
1019 1099
1020 1100
1021 1101
1022
crossed over to the APM group in the first 6 months and short-term (6-month) follow-up and no difference at 1102
1023 had similar WOMAC scores to the APM group, indicating 12-month follow-up compared with conservative 1103
1024 that they were at no disadvantage by prolonged con- treatment [87]. In addition, there was no significant 1104
1025 1105
1026 servative management before undergoing APM [73]. difference in pain scores using the KOOS pain subscale 1106
1027 Several meta-analyses examining randomized and the visual analog scale (VAS) between the groups. 1107
1028 1108
1029
controlled APM trials have not demonstrated long- Furthermore, a common theme identified in these 1109
1030 term benefit for pain relief or functional improve- meta-analyses is a high risk of bias in most included 1110
1031 ment in patients with degenerative meniscal tears randomized trials owing to lack of blinding to surgical 1111
1032 1112
1033 [84-87]. One recent study by van de Graaf et al [87] intervention. It has been suggested that the bias 1113
1034 observed the results of APM in 5 randomized created from a perceived lack of intervention in pa- 1114
1035 1115
1036
controlled trials [73,75,82,88-90], which included tients assigned to exercise-only groups could result in 1116
1037 1477 patients. Similar to the other meta-analyses, crossing over from physical therapy to APM after 1117
1038 results of this study showed only small significant failed conservative management [83]. These cross- 1118
1039 1119
1040 differences in LKSS, WOMAC, and KOOS scores during over rates can be as high as 21%-30% at 6-14 months 1120

1121 [72,73,91]. Patients who crossed over eventually ob- tears, vertical tears, red-red zone tears, no mechanical 1201
1122 1202
1123 tained outcomes similar to the APM group [73], which misalignment, and tears longer than 1 cm but shorter 1203
1124 could support the notion that APM remains an option than 4 cm [106]. Peripheral tears in the red-red zone are 1204
1125 1205
1126
after failed conservative management. However, the more amenable to repair because they are closest to the 1206
1127 placebo effect of having received a requested surgical peri-meniscal capillary plexus [103,105]. Failure rates 1207
1128 intervention also can lead to a bias regarding pa- have been shown to be as high as 70% at second-look 1208
1129 1209
1130 tients’ subjective postoperative pain and functional arthroscopy after inside-out repair of radial and obli- 1210
1131 status [83]. que tears that did not extend into the red-red zone 1211
1132
1133
One study by Gauffin et al [72] in 2014 compared APM [107]. Horizontal tears also have been traditionally 1212 1213
1134 with a 3-month home exercise program taught by considered poor candidates for repair [105], although 1214
1135 physiotherapists in middle-aged patients with confirmed new techniques have shown similar outcomes to other 1215
1136 1216
1137 meniscal tears and “meniscal symptoms.” They found tear patterns [108]. Repair techniques can be 1217
1138 significant differences in KOOS pain score at 12 months augmented through the use of fibrin clot or techniques 1218
1139 1219
1140 in the exercise and APM groups, with a between-group such as trephination or rasping. If direct repair is not 1220
1141 change supporting the APM group of 10.6 (confidence possible, then meniscal allograft transplantation (MAT) 1221
1142 1222
1143
interval 3.4-17.7, P ¼ .004). However, this study and scaffolding also might be options. 1223
1144 included only patients with an Ahlback radiologic oste- There is a wide variety of direct repair techniques 1224
1145 oarthritis grade of 0, corresponding to no radiographic involving the use of sutures to stabilize the torn 1225
1146 1226
1147 sign of osteoarthritis [92]. This is an important distinc- meniscus and these techniques can be very successful if 1227
1148 tion because degenerative meniscal tears are commonly used in the optimal patient. Direct repair techniques 1228
1149
1150
found in the setting of osteoarthritis regardless of active can be stratified based on open vs arthroscopic tech- 12291230
1151 meniscal symptoms [81,93]. Because arthroscopic sur- nique and the direction of suture placement (eg, 1231
1152 gery for the management of osteoarthritis has been well outside-in, inside-out, and all-inside). The inside-out 1232
1153 1233
1154 established as ineffective, including when performing technique is considered the “gold standard” for menis- 1234
1155 concurrent debridement of torn meniscal tissue [94,95], cal repair, although all-inside techniques continue to 1235
1156
1157
it can be inferred that performing APM for degenerative evolve [109]. Overall, research comparing meniscec- 1236 1237
1158 meniscal tears in the setting of osteoarthritis will lead tomy with meniscal repair is limited as demonstrated in 1238
1159 to minimal long-term improvement in pain and function. a recent meta-analysis that identified only 7 eligible 1239
1160 1240
1161 Previous studies regarding APM in the setting of studies to review, only 1 of which was a randomized 1241
1162 degenerative meniscal tears not only found a lack of prospective trial [110]. Three studies showed signifi- 1242
1163 1243
1164 long-term functional outcome and pain but also noted cantly improved LKSS scores in the repair group and 4 1244
1165 increased future risk of osteoarthritis [96-98]. Factors studies reported less activity loss in the repair group 1245
1166
contributing to this risk included the amount of meniscal using Tegner Activity scores [110]. One retrospective 1246
1167 1247
1168 tissue resected [99], compartment involved, tear study comparing 10-year outcomes of 32 patients with a 1248
1169 orientation, pre-existing chondral damage, ACL insuffi- mean age of 33 years who underwent APM vs meniscal 1249
1170 1250
1171 ciency, knee alignment, body habitus, age older than 40 repair showed significantly higher KOOS scores in pain, 1251
1172 years, and activity level [100]. This trend also was seen activity of daily living, and sports and recreation sub- 1252
1173
1174
in elite athletes, with a mean age of just 22.8 years, scales in the meniscal repair group. It also showed 1253 1254
1175 who had imaging of the knee performed at the National significantly lower grade of osteoarthritis, with a me- 1255
1176 Football League combine because of a history of knee dian Kellgren-Lawrence osteoarthritis grade of 0 (vs 2 1256
1177 1257
1178 surgery. The rate of osteoarthritis was highest in ath- for APM group) [111]. In addition to the increased 1258
1179 letes who had previous partial meniscectomy, noted to functional outcome and decreased complications in 1259
1180
1181
be 27% in this young, athletic population [101]. meniscal repair vs partial meniscectomy, the financial 1260
1261
1182 Furthermore, Rongen et al [102] reported that the burden of partial meniscectomy is much greater than 1262
1183 hazard ratio for receiving a total knee replacement was that of meniscal repair. In a cost analysis done in 2016 1263
1184 1264
1185 3.0 in patients who previously had APM compared with a by Feeley et al [112], it was estimated that patients who 1265
1186 risk-matched cohort who did not undergo APM. receive meniscal repair vs APM would save more than 1266
1187 1267
1188 $2000 over the course of treatment. In addition, a 10% 1268
1189 Direct Meniscal Repair decrease in APM rate would equate to an estimated 1269
1190
1191
health care savings of $43 million annually. Although 1270
1271
1192 Attempts to preserve the meniscus have increased in direct meniscal repair has been shown to have an 1272
1193 popularity because of its functional importance to the increased rate of failure compared with partial menis- 1273
1194 1274
1195 knee and risk of long-term osteoarthritis associated with cectomy (RR 4.37), the overall financial savings and Q3 1275
1196 meniscectomy. Not all meniscal tears are repairable. increased quality-adjusted life years make it a dominant 1276
1197 1277
1198
Typical guidelines based on previous literature [103-105] treatment strategy for most patients with reparable 1278
1199 used to identify patients who will have a successful tears to decrease risk of osteoarthritis and decrease 1279
1200 surgical repair include age younger than 40 years, acute financial burden. 1280

1281 Despite the use of optimal patients, meniscal repair LKSS score and International Knee Documentation 1361
1282 1362
1283 failure rate at more than 5 years remains 22.3%-24.3% Committee (IKDC) knee score. Although the use of fibrin Q4 1363
1284 [113], which encourages the use of augmentation clot to augment direct repair of meniscal tears is 1364
1285 1365
1286
techniques. Interestingly, meniscal tears in the setting promising, there are currently no level I studies on fibrin 1366
1287 of ACL tears exhibit improved outcomes compared with clot augmentation and additional research is needed to 1367
1288 meniscus tears alone [103,114,115], leading to the demonstrate its efficacy in treating meniscal tears. 1368
1289 1369
1290 conclusion that intra-articular blood and marrow MAT is a promising surgical treatment option for 1370
1291 release created by the ACL tunnel might be augmenting relatively young patients with knee pain after total 1371
1292
1293
meniscal healing. In a similar fashion, trephination and meniscectomy who are not candidates for knee arthro- 1372 1373
1294 rasping are 2 techniques used to induce vascular growth plasty [122]. Nevertheless, current literature is limited 1374
1295 and healing, especially in the red-white and white- because of different available allograft preservation 1375
1296 1376
1297 white regions. These techniques involve the creation and surgical techniques, resulting in high variability in 1377
1298 of vascular access channels from the peripheral vascular outcomes [123]. MAT also has limited use in the setting of 1378
1299 1379
1300 rich areas to the central avascular regions of the osteoarthritis and typically requires concurrent surgical 1380
1301 menisci. Trephination is performed by puncturing the procedures to correct malalignment or instability of the 1381
1302
1303
meniscus and extending the inner rim and substance of knee joint. Furthermore, patients are typically limited in 1382
1383
1304 the tear into the capsule [116]. It has been shown that their ability to return to high-impact sports [122]. A 1384
1305 direct meniscal repair augmented with trephination has recent review of 39 studies [122] concluded that, despite 1385
1306 1386
1307 a significantly decreased risk of failure compared with the difficult comparison secondary to large variability, 1387
1308 direct suturing alone [117]. In a study by Zhang and MAT can result in significant relief of pain and improve- 1388
1309
1310
Arnold [117], 28 patients received suturing only and 36 ment in function in a large percentage of patients, with 1389 1390
1311 received sutures plus trephination. At 78-month follow- longstanding improvement in approximately 70% of pa- 1391
1312 up, 6% of patients with trephination plus sutures had tients. All included studies were limited by a lack of 1392
1313 1393
1314 symptomatic re-tear compared with 25% of patients controlled comparison. Reported transplant failure and 1394
1315 with sutures only (P < .01). Furthermore, 27 of 30 pa- reoperation rates also vary considerably, averaging 18.7% 1395
1316
1317
tients in another case series with vertical and longitu- and 31.3%, respectively [123]. MAT also is not considered 13961397
1318 dinal meniscal tears who underwent trephination curative in the long term because 15-year failure rates 1398
1319 procedures without direct meniscal repair showed a were reported to be as high as 81% [124]. 1399
1320 1400
1321 significant increase in LKSS score and satisfactory sub- Meniscal scaffolding involves the use of collagen 1401
1322 jective return to function [116]. Although typically meniscal implants or polymer scaffolds to manage knee 1402
1323 1403
1324 performed arthroscopically, trephination also can be pain after partial or total meniscectomy and help prevent 1404
1325 performed under sonographic guidance given its accu- the progression of joint degeneration. In addition, it 1405
1326
racy in safely performing intrameniscal injections [118]. avoids the need for tissue banks or complex sizing pro- 1406
1327 1407
1328 Similar to trephination, rasping techniques use abrasion cedures such as in MAT [125]. The 2 scaffolds currently 1408
1329 from the peri-meniscal synovium toward the avascular available for commercial use are the Collagen Meniscal 1409
1330 1410
1331 region of the menisci to stimulate growth factor release Implant (CMI, Ivy Sports Medicine, Gräfelfing, Germany) 1411
1332 and healing. Uchio et al [55] found rasping techniques and the Actifit polyurethane scaffold (Actifit, Orteq Ltd, 1412
1333
1334
induced complete healing in 71% of patients with full- London, UK). The CMI is made of type I collagen from an 1413 1414
1335 and partial-thickness lateral and medial meniscal tears. Achilles tendon and is suitable for use in patients who 1415
1336 Notably, the extent of healing was affected by the have had more than 50% of their meniscus resected, 1416
1337 1417
1338 length of the original lesion and the distance to the joint allowing for meniscal tissue to grow into the implant 1418
1339 capsule. Potential drawbacks of the trephination and [126]. In like manner, the Actifit allows for tissue ingrowth 1419
1340
1341
rasping techniques are the possible damage the but is meant to slowly degrade over a 5-year period [127]. 1420
1421
1342 procedures cause to the meniscus and effects on Long-term prospective cohort studies have shown stati- 1422
1343 biomechanical properties, thus increasing risks for self- cally significant improvements in VAS, IKDC, and Tegner 1423
1344 1424
1345 collapse, channel closure, and delayed healing [119]. index scores at 10 years compared with partial menis- 1425
1346 Exogenous fibrin, in the form of powder, glue, or cectomy alone [125]. However, the current literature 1426
1347 1427
1348 clots, has been used in the operating room since 1909 to supporting the use of meniscal scaffolding is limited 1428
1349 promote hemostasis and accelerate postoperative because of the few available independent studies [123] 1429
1350
1351
healing [120]. It also has been used to augment meniscal but remains a promising option for patients with large 1430
1431
1352 repairs through the activation of platelets and promot- meniscal lesions. 1432
1353 ing the release of platelet-derived growth factors, in- 1433
1354 1434
1355 terleukins, angiogenesis factors, and endothelial growth Addressing the Treatment GapdOrthobiologics 1435
1356 factors [120]. In 2013, Ra et al [121] reported full 1436
1357 1437
1358
healing of complete radial tears in 12 patients after Because certain orthopedic surgeries have failed to 1438
1359 direct suturing augmented by fibrin clot. At 2-year demonstrate significant benefit in relieving pain or 1439
1360 follow-up all patients had significant improvement in restoring function after a musculoskeletal injury, 1440

1441 patients have begun to explore novel treatments to and synthesis of a glycosaminoglycan-rich extracellular 1521
1442 1522
1443 improve their conditions. Orthobiologics can be defined matrix. 1523
1444 as substances used with a therapeutic goal of enhancing Intrameniscal injections of PRP have the ability to 1524
1445
1446
or aiding the body’s ability to repair or regenerate attenuate pain associated with meniscal lesions and 1525 1526
1447 musculoskeletal tissue. Research on stem cell and cell- augment direct meniscal repair. Blanke et al [136] 1527
1448 based therapies has greatly evolved during the past 2 conducted a study involving 10 recreational athletes 1528
1449 1529
1450 decades, as has research on orthobiologic applications. with grade 2 intra-substance meniscal lesions. These 10 1530
1451 We believe there is a distinct treatment gap in patients patients underwent percutaneous intrameniscal in- 1531
1452
1453
with degenerative meniscal tears, who have not respon- jections of PRP and were followed up 6 months after the 1532
1533
1454 ded to conservative management, and who are not can- procedure. The average pain numeric rating scale score 1534
1455 didates for direct meniscal repair. These patients (11 points) significantly improved from 6.7 to 4.5 6 1535
1456 1536
1457 eventually might be offered APM because of a perceived months after treatment (P ¼ .027). In addition, 6 of the 1537
1458 lack of available treatment options. Such patients would 10 patients reported an increase in sports activity 1538
1459 1539
1460 benefit most from innovative treatments for meniscal compared with their activity levels before injections. 1540
1461 tears, such as the use of PRP, MSCs, or micro-fragmented Moreover, a recent case report described the efficacy of 1541
1462
1463
adipose tissue (MFAT). PRP in a patient with a grade 3a medial meniscus tear. 1542
1543
1464 These patients were followed for 30 months after 1544
1465 Platelet-rich Plasma treatment and reported significant improvement in pain 1545
1466 1546
1467 symptoms from baseline (VAS score ¼ 70 mm; Global 1547
1468 The use of PRP as a therapeutic technique to manage Rating of Change [GROC] score not available; KOOS Q5 1548
1469
1470
musculoskeletal injuries continues to increase in popu- score ¼ 39) to 30 months (VAS score ¼ 40 mm; GROC 1549 1550
1471 larity and indications [128], with strong evidence for its score ¼ 5; and KOOS score ¼ 63.1) [137]. More recently, 1551
1472 use in knee osteoarthritis [129,130]. Nevertheless, cur- a double-blinded randomized controlled trial was per- 1552
1473 1553
1474 rent evidence for the use of PRP in treatment of formed using PRP to augment direct meniscal repair of 1554
1475 meniscal tears is limited but encouraging. Platelets are vertical longitudinal tears. These tears were longer than 1555
1476
1477
known to release biomolecules and more than 1500 10 mm and in the red-white zone of the meniscus; red- 15561557
1478 different proteins, including growth factors, cytokines, zone tears were excluded. The primary outcome of 1558
1479 and chemokines, are contained in the platelet releasate meniscus healing as determined by second-look 1559
1480 1560
1481 [131]. These products have a myriad of roles, including arthroscopy or 1.5-T MRI showed 85% healing in the 1561
1482 recruitment, proliferation, and maturation of cells, to PRP group vs 47% in the saline control (P ¼ .048). The 1562
1483 1563
1484 facilitate regeneration of the tendon, ligament, muscle, PRP group also showed significant differences in IKDC, 1564
1485 bone, and cartilage [131]. Multiple anabolic growth WOMAC, and all 5 KOOS subscale scores compared with 1565
1486 1566
factors have important roles in healing after a lesion of control [138].
1487 1567
1488 the meniscus, with greater effect in the avascular zone 1568
1489 of the meniscus because of its inherently poor ability to Mesenchymal Stem Cells 1569
1490 1570
1491 heal [132]. These include vascular endothelial growth 1571
1492 factor-A, insulin-like growth factor-1, transforming MSCs are a subset of stem cells that have been iso- 1572
1493 1573
1494
growth factor-b1, platelet-derived growth factor-B, and lated from bone marrow (BM) [139], periosteum, 1574
1495 IL-1b [67,133]. PRP represents an autologous source of trabecular bone, adipose tissue [140,141], skeletal 1575
1496 these and other growth factors that could improve muscle, and deciduous teeth [142]. These cells have 1576
1497 1577
1498 repair and regeneration of medial meniscal lesions generated considerable interest in their clinical appli- 1578
1499 [132]. Moreover, PRP has been shown to inhibit the cations to regenerative medicine because of their abil- 1579
1500 1580
1501
negative inflammatory-mediated effects of osteoar- ity to participate in a number of cellular processes, 1581
1502 thritis on chondrocytes [134]. including tissue homeostasis, remodeling, and repair 1582
1503 Ishida et al [135] examined in vitro monolayer Lapine [143,144]. It has been proposed that MSCs in adult tis- 1583
1504 1584
1505 meniscal cell cultures in a rabbit model to assess the sues represent reservoirs of reparative cells that are 1585
1506 proliferation, extracellular matrix synthesis, and mRNA ready to differentiate in response to wound repair sig- 1586
1507 1587
1508 expression that occurred after exposure to a PRP prod- nals and disease states [143]. MSCs were first isolated 1588
1509 uct. A gelatin hydrogel scaffold was used as drug de- from BM in the late 1960s [145] and subsequent studies 1589
1510 1590
1511
livery for growth factors secreted by PRP to enhance have found these multipotent cells can form other cell 1591
1512 healing of meniscal defects. The meniscal lesions types such as adipocytes, osteoblasts, and chondrocytes. 1592
1513 showed a significant increase in fibrochondrocytes, DNA Human adipose-derived stem cells (ASCs) have more 1593
1514 1594
1515 synthesis, extracellular matrix synthesis, and greater recently been recognized and possess the ability to 1595
1516 mRNA expression of biglycan and decorin meniscal cells differentiate into adipocytes, osteoblasts, and chon- 1596
1517 1597
1518
compared with platelet-poor plasma and controls [135]. drocytes [146,147]. Recent studies have shown that ASCs 1598
1519 Their findings suggested that the combination of are not only easier to isolate from the body than BM- 1599
1520 hydrogel and PRP supports meniscal cell proliferation derived MSCs but also appear in higher concentrations 1600

1601 [141]. Here, we elucidate the various roles of BM-derived medicine. ASCs can be isolated from subcutaneous adi- 1681
1602 1682
1603 MSCs and ASCs in the repair of meniscal tears. pose tissue of the abdomen, thigh, and arm. Compared 1683
1604 Studies have reported successful repair of meniscal with BM, adipose tissue has been shown to yield more 1684
1605 1685
1606
punch defects in the avascular zone with a MSC- stem cells. One gram of aspirated adipose tissue yields 1686
1607 biomaterial combination on a hyaluronan-collagen base. approximately 500 times the amount of MSCs isolated 1687
1608 Zellner et al [148] created a circular 2-mm punch from a gram of BM aspirate [151]. In similar fashion to 1688
1609 1689
1610 meniscal defect in the avascular zone of rabbit meniscus, MSCs, ASCs have shown the capability to secrete various 1690
1611 which was then left empty or treated with biodegradable growth factors including vascular endothelial growth 1691
1612 1692
1613
hyaluronan-collagen composite matrices. These defects factor and hepatocyte growth factor [141]. These 2 1693
1614 were loaded with PRP, BM, BM-derived MSCs pre-cultured growth factors also promote neovascularization, a 1694
1615 in chondrogenic medium for 2 weeks, or BM-derived MSCs mechanism through which ASCs promote host tissue 1695
1616 1696
1617 without any pre-culture. Defects that were left empty or repair [152]. Previous studies have elucidated the benefit 1697
1618 treated without cells showed muted growth, whereas of ASCs to promote revascularization of ischemic mouse 1698
1619 1699
1620 uncultured MSC-loaded scaffolds showed defect filling hind limbs through hepatocyte growth factor secretion 1700
1621 with meniscus-like tissue. Although limited in use owing [153] and repair of scarred myocardium [152,154], indi- 1701
1622 1702
1623
to the animal model, MSCs appeared to be able to stim- cating that it could be of use in the avascular portion of 1703
1624 ulate the growth of meniscus-like tissue [148]. the meniscus. Also, like MSCs, ASCs express markers, such 1704
1625 There is early high-level evidence for use of BM- as CD13, CD29, CD44, CD63, CD73, CD90, and CD105. They 1705
1626 1706
1627 derived MSCs in management of knee pain after partial also are negative for hematopoietic antigens, such as 1707
1628 meniscectomy. A randomized, double-blinded, controlled CD14, CD31, CD45, and CD144 [155]. 1708
1629 1709
1630
study was conducted by Vangsness et al [149] involving 55 In vitro studies have demonstrated the regenerative 1710
1631 patients who underwent a partial medial meniscectomy potential of ASCs, including its differentiation into 1711
1632 followed by an injection 7-10 days later. They were chondrogenic and osteogenic cells. Several studies have 1712
1633 1713
1634 randomly assigned to treatment with 50 million (group A) investigated clinical outcomes of ASCs injected into 1714
1635 or 150 million (group B) BM-derived allogenic MSCs sus- rabbit osteoarthritis models. After 16 and 20 weeks, 1715
1636 1716
1637
pended in a sodium hyaluronate suspension compared rabbits receiving ASCs showed lower degrees of carti- 1717
1638 with suspension alone (group C). Twenty-four percent of lage degeneration, osteophyte formation, and sub- 1718
1639 patients in group A and 6% of patients in group B showed a chondral sclerosis than the non-ASC control group [156]. 1719
1640 1720
1641 significant meniscal volume gain at quantitative MRI Van Pham et al [157] induced osteoarthritis in mice by 1721
1642 (threshold defined as 15%) after 1 year. No patients in needle disruption and pretreated the joint space with 1722
1643 1723
1644 group C met the threshold of gaining significant meniscal PRP. They concluded that PRP-pretreated ASCs 1724
1645 volume. In addition, this study found that high doses of improved healing of injured articular cartilage in murine 1725
1646 1726
allogeneic MSCs could be safely injected into the knee models compared with that of untreated ASCs. Ude et al
1647 1727
1648 joint without ectopic tissue formation. VAS pain scores [158] compared ASCs and BM stem cells in a surgically 1728
1649 and LKSS scores showed significant and sustained im- induced sheep osteoarthritis model via ACL tear and 1729
1650 1730
1651 provements in all groups up to 2 years. There were no medial meniscectomy and found that the proliferation 1731
1652 significant intergroup differences except for significant rate of ASCs was significantly higher than that of BM 1732
1653 1733
1654
decreases in pain in patients with evidence of osteoar- stem cells. However, chondro-induced BM stem cells 1734
1655 thritis changes of the knee at baseline compared with had significantly higher expression of chondrogenic- 1735
1656 control [149]. More recently, a prospective case study specific genes compared with those of chondrogenic 1736
1657 1737
1658 examined the use of MSCs in augmenting direct meniscal ASCs. In addition, tracking dye (PKH26) fluorescence in 1738
1659 repair in a series of 5 patients. BM-derived MSCs placed in the injected cells showed that they had populated the 1739
1660 1740
1661
a collagen scaffold were arthroscopically implanted into a damaged area of cartilage. 1741
1662 meniscal tear before suture repair. The patients were There is a limited amount of literature describing the 1742
1663 followed for 24 months and showed clinical improvements use of ASCs for the regeneration of the meniscus in 1743
1664 1744
1665 on the Tegner-Lysholm score and the IKDC score at 24 humans. Pak et al [159] published a safety cohort report 1745
1666 months. However, 2 of the patients eventually pursued in which 91 patients with hip or knee pain and radiologic 1746
1667 1747
1668 partial meniscectomy because of re-tear vs nonhealing of evidence of degenerative joint disease were treated 1748
1669 the meniscal tear [150]. with an intra-articular mixture of ASCs, PRP, and a hy- 1749
1670 1750
1671
aluronic acid scaffold. Patients showed significant im-
1751
1672 Adipose-derived Stem Cells provements in pain at 3 months and complications were 1752
1673 limited to localized pain and swelling or tenosynovitis. A 1753
1674 1754
1675 ASCs are MSCs obtained from adipose tissue and have subsequent review by the same group reported that 32 1755
1676 the capacity to differentiate into multiple cell lineages of patients who had evidence of meniscal tears also 1756
1677 1757
1678
[146,147]. ASCs were first identified as MSCs in adipose demonstrated significant improvements in pain and 1758
1679 tissue in 2001 and have since been studied as a cell function [160]. They also reported on a 2014 case study 1759
1680 source for tissue engineering and regenerative in which a 32-year-old woman with a grade 2 medial 1760

1761 meniscal tear in the posterior horn was injected with a A new device for processing and transfer of adipose 1841
1762 1842
1763 similar combination of ASCs, PRP, hyaluronic acid, and tissue into MFAT has recently been approved by the FDA 1843
1764 calcium chloride, with 4 additional doses of PRP with [176]. The process involves a closed, full-immersion, 1844
1765 1845
1766
calcium chloride and hyaluronic acid at days 3, 7, 14, low-pressure cylindrical system designed to harvest, 1846
1767 and 28. Repeat MRI at 3 months showed near-complete process, and transfer refined adipose tissue. Therefore, 1847
1768 repair of her torn meniscus and improvement in pain it qualifies as minimally manipulated under FDA 1848
1769 1849
1770 and function [141]. Although the results are positive, it guidelines because it uses mild mechanical forces to 1850
1771 is difficult to draw conclusions regarding the dosing, micro-fragment fat tissue and wash away any proin- 1851
1772 1852
1773
regimen, or effect of any one treatment used in these flammatory oil and blood residues without the use of 1853
1774 studies given their simultaneous use. enzymes, additives, or separation centrifugation while 1854
1775 preserving the microarchitecture [177]. However, there 1855
1776 1856
1777 Micro-fragmented Adipose Tissue is controversy regarding the qualification of this device 1857
1778 and other MFAT harvesting techniques as “homologous 1858
1779 1859
1780 There are different methods to process autologous use” in certain orthopedic applications [173]. At this 1860
1781 adipose into MFAT with minimal manipulation and avoid- time, there are ongoing studies accessing the efficacy of 1861
1782 1862
1783
ing the use of enzymes [161-164]. Processed MFAT has this system in the treatment of meniscal tears. 1863
1784 been used as regenerative treatment for the management 1864
1785 of musculoskeletal conditions such as knee osteoarthritis 1865
1786
Conclusion 1866
1787 [165-167], shoulder pain secondary to osteoarthritis and 1867
1788 rotator cuff tear [168], and osteochondral defects of the The menisci are important fibrocartilaginous struc- 1868
1789 1869
1790
talus [169]. In addition, case reports have reported tures with limited blood supply and capabilities of 1870
1791 improvement in pain and function scores after intra- healing after injury. Conservative management com- 1871
1792 articular injection of MFAT in the setting of knee osteo- 1872
1793 bined with physical therapy remains a successful op- 1873
1794 arthritis and meniscal tear [170,171]. Furthermore, a case tion for mitigating pain and functional deficits after a 1874
1795 report has been presented on this use of this device in the 1875
1796
meniscal tear but does not directly address the 1876
1797
successful treatment of a degenerative meniscal tear in a meniscal tear. Historically, patients who have not 1877
1798 triathlete [172]. MFAT has been shown to have larger responded to conservative management have been 1878
1799 percentages of pericytes and human MSCs compared with 1879
1800 treated with APM; however, recent evidence has sug- 1880
1801 unprocessed fat graft, possibly contributing to its regen- gested that this surgery is no better than physical 1881
1802 erative potential [163]. 1882
1803
therapy or sham surgery and can result in increased 1883
1804 joint loading and progression of degenerative arthritis. 1884
1805 U.S. Food and Drug Administration Considerations This results in not only a great monetary cost to the 1885
1806 1886
1807 health care system but also functional limitations in 1887
1808 In light of the growing interest of allogeneic stem patients. Direct meniscal repair and replacement 1888
1809 cells for therapeutic use, several concerns have arisen 1889
1810
techniques show promise but are limited in their 1890
1811 regarding the safety, potential for contamination, and applicability at this time. Recent research has shown 1891
1812 manipulation of these products. One concern raised by that the use of regenerative treatments such as PRP, 1892
1813 1893
1814
the U.S. Food and Drug Administration (FDA) is the MSCs, or MFAT might stimulate healing of the meniscus 1894
1815 concept of “manipulation,” which refers to altering the and justify further research in their application alone 1895
1816 inherent structural or biological nature or structure of 1896
1817 or combined with procedures such as meniscal repair, 1897
1818 the product [173]. For example, enzymatic dissociation replacement, or trephination. 1898
1819 of adipose tissue to isolate ASCs would be classified as 1899
1820 1900
1821
“more than minimal manipulation” [174]. Concerns 1901
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P.S.C. Department of Physical Medicine and Rehabilitation, New Jersey Medical G.A.M. New Jersey Regenerative Institute LLC, 197 Ridgedale Avenue, #210,
2573 2658
2574 School, Rutgers University, Newark, NJ Cedar Knolls, NJ 07927; Department of Physical Medicine and Rehabilitation, 2659
2575 Disclosures: nothing to disclose New Jersey Medical School, Rutgers University, Newark, NJ. Address corre- 2660
2576 spondence to: G.A.M.: e-mail: gmalangamd@hotmail.com 2661
2577 S.J. Saba University School of Medicine, The Bottom, Saba, Dutch Caribbean Disclosures: consultancy, Lipogems Corp; payment for lectures including service 2662
2578 Disclosures: nothing to disclose on speaker’s bureaus, Lipogems Corp 2663
2579 2664
2580 Disclosures related to this publication: consulting fee or honorarium, Lipogems 2665
2581 S.I. New Jersey Medical School, Rutgers University, Newark, NJ Corp (G.A.M.) Q10 2666
2582 Disclosures: nothing to disclose 2667
2583 Submitted for publication March 30, 2018; accepted August 11, 2018. 2668
2584 H.E.W. New Jersey Medical School, Rutgers University, Newark, NJ 2669
2585 Disclosures: nothing to disclose 2670
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Treatment of Knee Meniscus Pathology: Rehabilitation, Surgery, and Orthobiologics

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Treatment of Knee Meniscus Pathology: Rehabilitation, Surgery, and Orthobiologics

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1 81

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161 strategy. In this article, we review meniscus anatomy, 241

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383 at magnetic resonance imaging (MRI) or arthroscopy 463

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801 Table 1 881

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