1. Rey-Rico A, Frisch J, Venkatesan JK, Schmitt G, Rial-
Hermida I, Taboada P, et al. PEO-PPO-PEO carriers
for rAAV-mediated transduction of human articular
chondrocytes in vitro and in a human osteochondral
defect model. ACS Appl Mater Interfaces. 2016;
8(32):20600-13.
2. Frisch J, Orth P, Venkatesan JK, Rey-Rico A, Schmitt
G, Kohn D, et al. Genetic modification of human
peripheral blood aspirates using recombinant adenoassociated
viral vectors for articular cartilage repair
with a focus on chondrogenic transforming growth
factor-β gene delivery. Stem Cells Transl Med. 2017;
6(1):249-60.
3. Hunziker EB. Articular cartilage repair: basic science
and clinical progress. A review of the current
status and prospects. Osteoarthr Cartilage. 2002;
10(6):432-63.
4. Rodriguez-Merchan EC. The treatment of cartilage
defects in the knee joint: Microfracture, mosaicplasty,
and autologous chondrocyte implantation. Am J
Orthop. 2012; 41(5):236-9.
5. Rodriguez-Merchan EC. Regeneration of articular
cartilage of the knee. Rheumatol Int. 2013;
33(4):837-45.
6. Veronesi F, Giavaresi G, Tschon M, Borsari V, Nicoli
Aldini N, Fini M, et al. Clinical use of bone marrow,
bone marrow concentrate, and expanded bone
marrow mesenchymal stem cells in cartilage disease.
Stem Cells Dev. 2013; 22(2):181-92.
7. Madry H, Grun UW, Knutsen G. Cartilage repair and
joint preservation: Medical and surgical treatment
options. Dtsch Arztebl Int. 2011; 108(40):669-77.
8. Ribeil JA, Hacein-Bey-Abina S, Payen E, Magnani
A, Semeraro M, Magrin E, et al. Gene therapy in a
patient with sickle cell disease. N Engl J Med. 2017;
376(9):848-55.
9. George LA, Sullivan SK, Giermasz A, Rasko JE,
Samelson-Jones BJ, Ducore J, et al. Hemophilia B gene
therapy with a high-specific-activity factor IX variant.
N Engl J Med. 2017; 377(23):2215-27.
10. Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-
Klapac LR, Prior TW, et al. Single-dose genereplacement
therapy for spinal muscular atrophy. N
Engl J Med. 2017; 377(18):1713-22.
11. Ondrésik M, Azevedo Maia FR, da Silva Morais
A, Gertrudes AC, Dias Bacelar AH, Correia C, et
al. Management of knee osteoarthritis. Current
status and future trends. Biotechnol Bioeng. 2017;
114(4):717-39.
12. Weisleder N, Takizawa N, Lin P, Wang X, Cao C, Zhang
Y, et al. Recombinant MG53 protein modulates
therapeutic cell membrane repair in treatment
of muscular dystrophy. Sci Transl Med. 2012;
4(139):139ra85.
13. Nagahara AH, Merrill DA, Coppola G, Tsukada S,
Schroeder BE, Shaked GM, et al. Neuroprotective
effects of brain-derived neurotrophic factor in rodent
and primate models of Alzheimer’s disease. Nat Med.
2009; 15(3):331-7.
14. Bartus K, James ND, Didangelos A, Bosch KD,
Verhaagen J, Yáñez-Muñoz RJ, et al. Large-scale
chondroitin sulfate proteoglycan digestion with
chondroitinase gene therapy leads to reduced
pathology and modulates macrophage phenotype
following spinal cord contusion injury. J Neurosci.
2014; 34(14):4822-36.
15. Kafienah W, Al-Fayez F, Hollande AP, Barker MD.
Inhibition of cartilage degradation: a combined tissue
engineering and gene therapy approach. Arthritis
Rheum. 2003; 48(3):709-18.
16. Evans CH, Gouze JN, Gouze E, Robbins PD, Ghivizzani
SC. Osteoarthritis gene therapy. Gene Ther. 2004;
11(4):379-89.
17. Nixon AJ, Saxer RA, Brower-Toland BD. Exogenous
insulin-like growth factor-I stimulates an
autoinductive IGF-I autocrine/paracrine response in
chondrocytes. J Orthop Res. 2001; 19(1):26-32.
18. Shi S, Mercer S, Trippel SB. Effect of transfection
strategy on growth factor overexpression by articular
chondrocytes. J Orthop Res. 2010; 28(1):103-9.
19. Yu P, Wang X, Fu YX. Enhanced local delivery with
reduced systemic toxicity: delivery, delivery, and
delivery. Gene Ther. 2006; 13(15):1131-2.
20. Bellavia D, Veronesi F, Carina V, Costa V, Raimondi
L, De Luca A, et al. Gene therapy for chondral and
osteoachndral regeneration: is the future now? Cell
Mol Life Sci. 2018; 75(4):649-67.
21. Shi S, Chan AG, Mercer S, Eckert GJ, Trippel SB.
Endogenous versus exogenous growth factor
regulation of articular chondrocytes. J Orthop Res.
2014; 32(1):54-60.
22. Li KC, Hu YC. Cartilage tissue engineering: recent
advances and perspectives from gene regulation/
therapy. Adv Healthc Mater. 2015; 4(7):948-68.
23. Steinert AF, Weissenberger M, Kunz M, Gilbert
F, Ghivizzani SC, Göbel S, et al. Indian hedgehog
gene transfer is a chondrogenic inducer of human
mesenchymal stem cells. Arthritis Res Ther. 2012;
14(4):R168.
24. Somoza RA, Wleter JF, Correa D, Kaplan AI.
Chondrogenic differentiation of mesenchymal stem
cells: challenges and unfulfilled expectations. Tissue
Eng Part B Rev. 2014; 20(6):596-608.
25. Lu CH, Yeh TS, Yeh CL, Fang YH, Sung LY, Lin SY, et
al. Regenerating cartilages by engineered ASCs:
prolonged TGF-b3/BMP-6 expression improved
articular cartilage formation and restored zonal
structure. Mol Ther. 2014; 22(1):186-95.
26. Frank KM, Hogarth DK, Miller JL, Mandal S, Mease
PJ, Samulski RJ, et al. Investigation of the cause of
death in a gene therapy trial. N Engl J Med. 2009;
361(2):161-9.

27. Evans CH, Ghivizzani SC, Robbins PD. Gene delivery
to joints by intra-articular injection. Hum Gene Ther.
2018; 29(1):2-14.
28. Ying J, Wang P, Zhang S, Xu T, Zhang L, Dong R, et al.
Transforming growth factor-beta1 promotes articular
cartilage repair through canonical Smad and Hippo
pathways in bone mesenchymal stem cells. Life Sci.
2018; 192(1):84-90.
29. Madry H, Zurakowski D, Trippel SB. Overexpression
of human insuli-like growth factor-1 promotes new
tissue formation in an ex vivo model of articular
chondrocyte transplantation. Gene Ther. 2001;
8(19):1443-9.
30. Madry H, Kaul G, Cucchiarini M, Stein U, Zurakowski
D, Remberger K, et al. Enhanced repair of articular
cartilage defects in vivo by transplanted chondrocytes
overexpressing insulin-like growth factor 1 (IGF-1).
Gene Ther. 2005; 12(15):1171-9.
31. Saxer RA, Bent SJ, Brower-Toland BD, Mi Z, Robbins
PD, Evans CH, et al. Gene mediated insulin-like growth
factor-1 delivery to the synovium. J Orthop Res. 2001;
19(5):759-67.
32. Madry H, Cucchiarini M. Advances and challenges in
gene-based approaches for osteoarthritis. J Gene Med.
2013; 15(10):343-55.
33. Hellgren I, Drvota V, Rieper R, Enoksson S, Blomberg
P, Islam KB, et al. Highly efficient cell-mediated gene
transfer using non-viral vectors and FuGene6: in vitro
and in vivo studies. Cell Mol Life Sci. 2000; 57(8-
9):1326-33.
34. Goodrich LR, Hidaka C, Robbins PD, Evans CH,
Nixon AJ. Genetic modification of chondrocytes
with insulin-like growth factor-1 enhances cartilage
healing in an equine model. J Bone Joint Surg Br.
2007; 89(5):672-85.
35. Brower-Toland BD, Saxer RA, Goodrich LR, Mi Z,
Robbins PD, Evans CH, et al. Direct adenovirusmediated
insulin-like growth factor 1 gene transfer
enhances transplant chondrocyte function. Hum Gene
Ther. 2001; 12(2):117-29.
36. Brigham, standard of care: autologous chondrocyte
implantation (ACI). Massachusetts, US: Brigham &
Women’s Hospital; 2007. P. 1-8.
37. Kalus W, Zweckstetter M, Renner Y, Sanchez Y,
Georgescu J, Grol M, et al. Structure of the IGF-binding
domain of the insulin-like growth factor-binding
protein-5 (IGFBP-5): implications for IGF and IGFreceptor
interactions. EMBO J. 1998; 17(22):6558-72.
38. Jones JI, Gockerman A, Busby WH, Camacho-Hubner C,
Clemmons DR. Extracellular matrix contains insulinlike
growth factor binding protein-5: potentiation of
the effects of IGF-1. J Cell Biol. 1993; 121(3):679-87.
39. Ducheyne P, Mauck RL, Smith DH. Biomaterials
on the repair of sports injuries. Nat Mater. 2012;
11(8):652-4.
40. Chen P, Mei S, Xia C, Zhu R, Pang Y, Wang J, et al.
The amelioration of cartilage degeneration by
photo-crosslinked GelHA hydrogel and crizotinib
encapsulated chitosan microspheres. Oncotarget.
2017; 8(18):30235-51.
41. Shi Q, Rondon-Cavanzo EP, Dalla Picola IP, Tiera MJ,
Zhang X, Dai K, et al. In vivo therapeutic efficacy of
TNFα silencing by folate-PEG-chitosan-DEAE/siRNA
nanoparticles in arthritic mice. Int J Nanomedicine.
2018; 13(12):387-402.
42. Shafiee A, Kabiri M, Langroudi L, Soleimani M,
Ai J. Evaluation and comparison of the in vitro
characteristics and chondrogenic capacity of four
adult stem/progenitor cells for cartilage cell-based
repair. J Biomed Mater Res A. 2016; 104(3):600-10.
43. Wang Y, Bian YZ, Wu Q, Chen GQ. Evaluation of
three-dimensional scaffolds prepared from poly(3-
hydroxybutyrate-co-3-hydroxyhexanoate) for growth
of allogeneic chondrocytes for cartilage repair in
rabbits. Biomaterials. 2008; 29(19):2858-68.
44. Chen J, Wang F, Zhang Y, Jin X, Zhang L, Feng Y, et al.
In vivo MRI tracking of polyethylenimine-wrapped
superparamagnetic iron oxide nanoparticle-labeled
BMSCs for cartilage repair: a minipig model. Cartilage.
2013; 4(1):75-82.
45. Dey P, Schneider T, Chiappisi L, Gradzielski M,
Schulze-Tanzil G, Haag R. Mimicking of chondrocyte
microenvironment using in situ forming dendritic
polyglycerol sulfate-based synthetic polyanionic
hydrogels. Macromol Biosci. 2016; 16(4):580-90.
46. Guo T, Zhao J, Chang Z, Ding Z, Hong H, Chen J, et al.
Porous chitosan-gelatin scaffold containing plasmid
DNA encoding transforming growth factor-771 for
chondrocytes proliferation. Biomaterials. 2006;
27(7):1095-103.
47. Zhao X, Yu SB, Wu FL, Mao ZB, Yu CL. Transfection
of primary chondrocytes using chitosan-pEGFP
nanoparticles. J Control Release. 2006; 112(2):223-8.
48. Thanou M, Florea BI, Geldof M, Junginger HE, Borchard
G. Quaternized chitosan oligomers as novel gene
delivery vectors in epithelial cell lines. Biomaterials.
2002; 23(1)153-9.
49. Richardson SM, Curran JM, Chen R, Vaughan-Thomas
A, Hunt JA, Freemont AJ, et al. The differentiation
of bone marrow mesenchymal stem cells into
chondrocyte-like cells on ply-l-lactic acid (PLLA)
scaffolds. Biomaterials. 2006; 27(22):4069-78.
50. Yao Y, He Y, Guan Q, Wu Q. A tetracycline expression
system in combination with Sox9 for cartilage tissue
engineering. Biomaterials. 2014; 35(6):1898-906.
51. Liu C, Zhang P, Zhai X, Tian F, Li W, Yang J, et al. Nanocarrier
for gene delivery and bioimaging based
on carbon dots with PEI-passivation enhanced
fluorescence. Biomaterials. 2012; 33(13):3604-13.
52. Chen XA, Zhang LJ, He ZJ, Wang WW, Xu B, Zhong Q, et
al. Plasmid-encapsulated polyethylene glycol-grafted
polythylenimine nanoparticles for gene delivery into
rat mesenchymal stem cells. In J Nanomed. 2011;
6(1):843-53.
53. Madry H, Cucchiarini M, Stein U, Remberger K, Menger
MD, Kohn D, et al. Sustained transgene expression
in cartilage defects in vivo after transplantation of
articular chondrocytes modified by lipid-mediated
gene transfer in a gel suspension delivery system. J
Gene Med. 2003; 5(6):502-9.
54. Rowley JA, Madlambayan G, Mooney DJ. Alginate
hydrogels as synthetic extracellular matrix materials.Biomaterials. 1999; 20(1):45-53.

55. Hern DL, Hubbell JA. Incorporation of adhesion
peptides into nonadhesive hydrogels useful for tissue
resurfacing. J Biomed Mater Res. 1998; 39(2):266-76.
56. Marcum JA, Rosenberg RD. Anticoagulopathy
active heparin-like molecules from vascular tissue.
Biochemistry. 1984; 23(8):1730-7.
57. Aguilar IN, Trippel S, Shi S, Bonasar LJ. Customized
biomaterials to augment chondrocyte gene therapy.
Acta Biomater. 2017; 53(1):260-7.
58. Shopia Fox AJ, Bedi A, Rodeo SA. The basic science
of articular cartilage: structure, composition, and
function. Sports Health. 2009; 1(6):461-8.
59. Buckwalter JA. Articular cartilage: Injuries and
potential for healing. J Orthop Sports Phys Ther. 1998;
28(4):192-202.
60. Zvaifler NJ, Marinova-Mutafchieva L, Adams G,
Edwards CJ, Moss J, Burger JA, et al. Mesenchymal
precursor cells in the blood of normal individuals.
Arthritis Res. 2000; 2(6):477-88.
61. Chong PP, Selvaratnam L, Abbas M, Kamarul T.
Human peripheral blood derived mesenchymal
stem cells demonstrate similar characteristics and
chondrogenic differentiation potential to bone
marrow mesenchymal stem cells. J Orthop Res. 2012;
30(4):634-42.
62. Skowronski J, Rutka M. Osteochondral lesions of the
knee reconstructed with mesenchymal stem cellsresults.
Ortop Traumatol Rehabil. 2013; 15(3):195-
204.
63. Saw KY, Anz A, Merican S, Tay YG, Ragavanaidu K, Jee CS,
et al. Articular cartilage regeneration with autologous
peripheral blood progenitor cells and hyaluronic acid
after arthroscopic subchondral drilling: a report of 5
cases with histology. Arthroscopy. 2011; 27(4):493-
506.
64. Saw KY, Anz A, Siew-Yoke Jee C, Merican S, Ching-Soong
Ng R, Roohi SA, et al. Articular cartilage regeneration
with autologous peripheral blood progenitor cells
versus hyaluronic acid: a randomized controlled trial.
Arthroscopy. 2013; 29(4):684-94.
65. Skowronski J, Skowronski R, Rutka M. Cartilage
lesions of the knee treated with blood mesenchymal
cells – results. Ortop Traumatol Rehabil. 2012;
14(6):569-77.
66. Frisch J, Orth P, Venkatesan JK, Rey-Rico A, Schmitt
G, Kohn D, et al. Genetic modification of human
peripheral blood aspirates using recombinant adenoassociated
viral vectors for articular cartilage repair
with a focus on chondrogenic transforming growth
factor-β gene delivery. Stem Cells Transl Med. 2017;
6(1):249-60.
67. Pascher A, Palmer GD, Steinert A, Oligino T, Gouze
E, Gouze JN, et al. Gene delivery to cartilage defects
using coagulated bone marrow aspirate. Gene Ther.
2004; 11(2):133-41.
68. Venkatesan JK, Frisch J, Rey-Rico A, Schmitt G, Madry
H, Cucchiarini M. Impact of mechanical stimulation on
the chondrogenic processes in human bone marrow
aspirates modified to overexpress sox9 via rAAV
vectors. J Exp Orthop. 2017; 4(1):22.
69. Grol MW, Lee BH. Gene therapy for repair and
regeneration of bone and cartilage. Curr Opin
Pharmacol. 2018; 40(1):59-66.
70. Bellavia D, Veronesi F, Carina V, Costa V, Raimondi
L, De Luca A, et al. Gene therapy for chondral and
osteochondral regeneration: is the future now? Cell
Mol Life Sci. 2018; 75(4):649-67.
71. Kim MK, Ha CW, In Y, Cho SD, Choi ES, Ha JK, et al. A
multicenter, double-blind, phase III clinical trial to
evaluate the efficacy and safety of a cell and gene
therapy in knee osteoarthritis patients. Hum Gene
Ther Clin Dev. 2018; 27(1):10.
72. Kim MK, Ha CW, In Y, Cho SD, Choi ES, Ha JK, et al. A
multicenter, double-blind, phase III clinical trial to
evaluate the efficacy and safety of a cell and gene
therapy in knee osteoarthritis patients. Hum Gene
Ther Clin Dev. 2018; 29(1):48-59.
73. Watson Levings R, Broome TA, Smith AD, Rice BL, Gibbs
EP, Myara DA, et al. Gene therapy for osteoarthritis:
pharmacokinetics of intra-articular scAAV.IL-1Ra
delivery in an equine model. Hum Gene Ther Clin Dev.
2018; 29(2):90-100.
74. Rodriguez-Merchan EC. Medial unicompartmental
osteoarthritis (MUO) of the knee: Unicompartmental
knee replacement (UKR) or total knee replacement
(TKR). Arch Bone Jt Surg. 2014; 2(3):137-40.
75. Rodriguez-Merchan EC. Unicompartmental knee
osteoarthritis (UKOA): unicompartmental knee
arthroplasty (UKA) or high tibial osteotomy (HTO)?
Arch Bone Jt Surg. 2016; 4(4):307-13.
76. Rodriguez-Merchan EC. Does a previous high tibial
osteotomy (HTO) influence the long-term function
or survival of a total knee arthroplasty (TKA)? Arch
Bone Jt Surg. 2018; 6(1):19-22.