Next Article in Journal
Drug Combination Studies of the Dipeptide Nitrile CD24 with Curcumin: A New Strategy to Synergistically Inhibit Rhodesain of Trypanosoma brucei rhodesiense
Next Article in Special Issue
Dysferlin Deficiency Results in Myofiber-Type Specific Differences in Abundances of Calcium-Handling and Glycogen Metabolism Proteins
Previous Article in Journal
BDE-47, -99, -209 and Their Ternary Mixture Disrupt Glucose and Lipid Metabolism of Hepg2 Cells at Dietary Relevant Concentrations: Mechanistic Insight through Integrated Transcriptomics and Proteomics Analysis
Previous Article in Special Issue
Dual Modification of Porous Ca-P/PLA Composites with APTES and Alendronate Improves Their Mechanical Strength and Cytobiocompatibility towards Human Osteoblasts
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 23
Issue 22
10.3390/ijms232214467
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Advanced Gene Therapy Strategies for the Repair of ACL Injuries

by
Mahnaz Amini
1,
Jagadeesh K. Venkatesan
1,
Wei Liu
1,
Amélie Leroux
2,
Tuan Ngoc Nguyen
2,
Henning Madry
1,
Véronique Migonney
2 and
Magali Cucchiarini
1,*
1
Center of Experimental Orthopaedics, Saarland University Medical Center, Kirrbergerstr. Bldg 37, D-66421 Homburg, Germany
2
Laboratoire CSPBAT UMR CNRS 7244, Université Sorbonne Paris Nord, Avenue JB Clément, 93430 Villetaneuse, France
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(22), 14467; https://doi.org/10.3390/ijms232214467
Submission received: 18 October 2022 / Revised: 7 November 2022 / Accepted: 19 November 2022 / Published: 21 November 2022
(This article belongs to the Special Issue Molecular and Tissue Engineering Approaches in Musculoskeletal Regenerative Medicine 4.0)
Browse Figures
Versions Notes

Abstract

:
The anterior cruciate ligament (ACL), the principal ligament for stabilization of the knee, is highly predisposed to injury in the human population. As a result of its poor intrinsic healing capacities, surgical intervention is generally necessary to repair ACL lesions, yet the outcomes are never fully satisfactory in terms of long-lasting, complete, and safe repair. Gene therapy, based on the transfer of therapeutic genetic sequences via a gene vector, is a potent tool to durably and adeptly enhance the processes of ACL repair and has been reported for its workability in various experimental models relevant to ACL injuries in vitro, in situ, and in vivo. As critical hurdles to the effective and safe translation of gene therapy for clinical applications still remain, including physiological barriers and host immune responses, biomaterial-guided gene therapy inspired by drug delivery systems has been further developed to protect and improve the classical procedures of gene transfer in the future treatment of ACL injuries in patients, as critically presented here.

1. Introduction

Injuries in the anterior cruciate ligament (ACL) of the knee are common, representing an important socioeconomical burden as they may occur both in young individuals following sport activities and in the aging population by chronic degeneration and result in diminished musculoskeletal functions and potentially leading to osteoarthritis [1,2,3]. Since the ACL has a slow and limited intrinsic ability for self-healing [2,4,5,6,7,8,9,10,11], various clinical options have been developed to enhance the reparative activities in sites of ACL injury, including conservative treatments and surgical interventions such as ACL reconstruction [11,12,13,14,15,16,17,18,19,20,21,22] using natural grafts (auto-/allografts) and synthetic materials [22,23,24,25,26,27,28,29]. Yet, none of these approaches afford the long-lasting healing of ACL lesions with original structural and mechanical features, and they can be associated with notable complications including pain, contractures, weakness, failure, re-ruptures, premature osteoarthritis, infections, and detrimental body responses [17,18,23,30,31,32,33,34,35,36,37,38,39,40,41].
To address these issues, novel therapeutic strategies were established to improve the mechanisms of ACL repair based on the further use of tissue engineering tools including adapted scaffolds (structural templates), cell-based material (reparative elements), bioreactors (environmental and loading control systems), and biological stimuli (regulatory factors and cues) [2,8,37,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72], yet application of these systems in experimental settings was met with only limited success and did not allow for full and durable ACL repair.
In this regard, gene therapy may provide adapted tools for an improved, prolonged healing of ACL lesions by transfer of candidate genetic sequences with a gene carrier (vector) to extend the therapeutic activities of the gene products (growth and transcription factors, signaling molecules, therapeutic ribonucleic acids—RNAs) in sites of ACL injury [73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93]. However, clinical gene therapy is still hindered by different physiological barriers in the recipient, including physical obstacles (body fluids, dense joint extracellular matrices) and biological inhibitors (pH/enzymatic environment of the joint, neutralizing host immune responses, rate-limiting intracellular steps, gene dissemination to non-target locations) [83,94,95,96,97,98]. A very innovative approach to tackle these problems is to provide therapeutic gene vectors via biomaterial-guided delivery in sites of ACL injury as an off-the-shelf system, allowing for a safe, stabilized, and protected controlled release of the gene vehicles using biocompatible scaffolds (cargos) [82,83,87,90,99,100,101,102,103,104]. The goal of this work is, therefore, to provide an overview of the most advanced gene therapy procedures that aim at enhancing the repair of ACL injuries.

2. ACL: Basic Science, Clinical Questions

2.1. ACL Function and Structure

The knee joint contains four ligaments that play key roles in kinematics and maintaining knee stability, connecting bones to each other, including two lateral ligaments that provide stability in the frontal plane and the anterior and posterior cruciate ligaments that support stability in the sagittal plane. Located in the center of the knee, the ACL forms part of the “central pivot” with the posterior cruciate ligament. The ACL is fundamental to connect the anterior part of the tibia to the posterior part of the femur, opposing forward displacement and excessive internal rotation of the tibia relative to the femur and stabilizing the knee during rotational movements [17,105,106,107] (Figure 1).
The ACL is a dense, cable-like tissue (27–32 mm in length, 10 mm in breadth, 4–10 mm in width, and 44.4–57.5 mm2 cross-sectional area) [46,105,108] that is highly organized, with an abundant extracellular matrix (ECM) mainly composed of collagens in fiber bundles (predominantly type-I collagen and types-III, -IV, -V, and -VI collagens; 70–80% dry weight) with elastin, fibronectin, thrombospondin, and proteoglycans (organization and lubrication of collagen fibril bundles) also surrounding ECM-producing cells (fibroblasts) in a hypocellular structure containing water (55–70%). The ACL has a hierarchical, sequentially assembled organization with increasing diameter and mechanical strength that includes collagen molecules (triple-helix polypeptide chains, <2 nm in diameter) that crosslink to form microfibrils (3.5 nm in diameter) that arrange themselves into subfibrils (10–20 nm in diameter) and then in fibrils (50–500 nm in diameter) that form fibers in fascicles (50–300 μm, with a crimp pattern repeated every 45–60 μm) that mutually crosslink to make a subfascicular unit running parallel to the long axis of the tissue, also containing proteoglycans and elastin and surrounded by a vascularized epiligament sheath to form the ligament [7,45,46,49,105,109,110,111,112] (Figure 2).
The cells in the ACL are interspersed between the collagen fibril bundles along the long axis, with a spindle-shaped form at an immature stage and a more elongated shape when they age. The ACL originates from the lateral plate mesoderm and its development is regulated by signaling from various growth factors (transforming growth factor beta—TGF-β—via TGFBR-receptor signaling and small mothers against decapentaplegic proteins—Smads; fibroblast growth factor—FGF—via FGFR-receptor signaling and extracellular signal-regulated kinase—ERK/mitogen-activated protein kinase—MAPK) and transcription factors (scleraxis—SCX—a basic helix-loop-helix factor; Mohawk—MKX—encoded by an atypical, three-amino-acid loop homeobox gene; early growth response factor 1—Egr1—a zinc finger transcription factor) that promote the differentiation of mesenchymal progenitor cells into ligament cells [11,105,113,114,115,116,117,118,119,120] (Figure 3).

2.2. Clinical Aspects: Pathology, Natural Healing, and Current Treatments

Ligament injuries are common, especially in the ACL (25–50% of knee ligamentous injuries; incidence of 1 per 3000 inhabitants per year in the United States and in Europe) [1]. ACL injuries are mainly derived from sport activities (65%) in the young population (70% of affected patients between 20–35 years old) and occur via chronic tissue degeneration in the aging population, both resulting in diminished musculoskeletal functions and potentially leading to osteoarthritis [1,35]. In the United States only, approximately 300.000 ACL reconstruction surgeries are performed annually, costing approximately USD 30 billion [2,3,10,60], clearly representing a significant public health problem.
The natural healing of ACL injuries is slow and inefficient, leading to the formation of scar tissue that does not naturally reproduce the original biological and mechanical properties of the tissue due to the limited intrinsic ability of the ACL to fully heal [2,4,5,6,7,8,10,11,13,14,15,16,46,54,121]. Three major cascade phases of ligament healing have been defined in response to injury, including (1) an inflammatory stage within the first days and weeks of injury (serous fluid accumulation, fragilization of the area, formation of a fibrin clot, invasion by monocytes/leukocytes/macrophages, debris removal, release of pro-angiogenic and proliferative growth factors and cytokines), (2) a proliferative stage by 8 weeks (blood vessel formation, fibroblast proliferation with collagen matrix production to fill up the injury), and (3) a remodeling phase between 1 and 2 years (decrease in cellularity, matrix realignment for adapted response to mechanical forces) [5,8]. The lack of proper ACL healing is due to the intra-articular conditions (synovial fluid, intra-articular movements) that hinder the stable formation of a fibrin/platelet scaffold (a prerequisite to primary healing), to an insufficient availability of reparative factors (growth factors and cytokines, wound filling compounds such as fibrinogen/fibronectin), to the lack of continuity between collagen fibers between the new and the old matrices leading to reduced tissue mechanical properties, and to the absence of vascularization of this ligament [2,5,8,10].
Due to the limited healing capacity of the ACL, a number of therapeutic options have been developed to restore its functions in the knee, including non-operative conservative treatments (immobilization/bracing/rest, exercise/physiotherapy, corticoid injection, etc.) and surgical procedures (ACL reconstruction, i.e., ligamentoplasty), while primary repair (suturing) was abandoned due to high rates of failure (40–100%) [2,11,12,17,18,19,20,21,22,23,37,60]. ACL reconstruction has been widely adopted as a standard procedure, especially for young patients, based on the use of both natural/biological grafts including autografts (patellar, hamstring, or quadriceps tendons) and allografts (frozen ligaments from cadavers), as well as commercially available synthetic or artificial materials and systems (substitutes, graft-augmented, and prosthetic devices) (Gore-Tex®—polytetrafluoroethylene—prosthesis; Lars® ligament—terephthalic polyethylene polyester; Stryker-Dacron® ligament—polyethylene terephthalate; Leeds-Keio®—polyester ethylene terephthalate; Kennedy ligament-augmentation device—LAD—braided polypropylene braid) [2,17,18,22,23,24,25,26,27,28,29,37,43,46,60,105,122]. While autografts display several advantages (good initial mechanical strength, adapted to promote cell proliferation and neotissue formation), their use is restricted by their limited availability, the necessity for second surgery for tissue harvest, the problem of donor site morbidity resulting in pain/contracture/weakness, and a lack of fully adequate mechanical strength over time [2,17,18,22,23,37,46,60]. Regarding allografts instead, second surgery for tissue harvest is not needed and there is no limit to the supply of graft tissue, generally allowing for good initial mechanical strength and supporting cell proliferation and neotissue formation. However, the use of allografts is associated with a possible transmission of diseases and infections, with potential host immunological foreign body responses, delayed biological integration, and a lack of fully adequate mechanical strength over time while their sterilization usually affects their mechanical properties [2,17,18,22,23,37,46,60]. Synthetic or artificial materials and systems have a number of advantages over natural grafts (availability, reproducibility, safety) but they may fail over time as they do not reliably reproduce the mechanical properties of the ACL, potentially leading to permanent deformation and degeneration upon repeated elongation with the creation of inflammatory debris in the joint [2,17,18,22,23,37,46,54,60]. While patients have benefited from ACL reconstruction, a significant percentage of them (20–25%) have unadapted and unsatisfactory outcomes and serious complications over time (7–10 years after surgery), including re-ruptures and premature osteoarthritic changes (50% incidence), both in young active patients and in elder individuals [9,30,31,32,33,34,36,38,39,40,41,123].

2.3. Experimental Treatments: Tissue Engineering and Biological Augmentation

As none of the current therapeutic interventions have, thus far, been capable of affording long-lasting ACL repair, other options have been envisaged to manage this critical clinical issue, including tissue engineering procedures and biological augmentation to replicate the natural environment of the ACL tissue and enhance its reparative activities based on the use of (1) biocompatible, biodegradable, minimally inflammatory, and mechanically adapted material scaffolds serving as structural and logistic templates, (2) cells and tissues providing reparative components, (3) bioreactors for loading and as control systems of the cellular environment, and (4) biological, biochemical, and biomechanical signals and nutrients as regulatory factors and cues [2,8,10,11,26,43,45,46,47,48,49,52,54,55,56,57,59,60,61,62,63,64,65,66,67,68,69,70,72,75,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149].
Biomaterial scaffolds used for ACL repair include systems (solutions, gels, fibers, membranes, matrices, sponges) based on fibrin [150,151], hyaluronic acid (HA) [152,153,154,155], chitosan [156], collagen [44,157,158,159,160,161,162,163,164,165,166,167,168], silk [169,170,171,172,173,174,175,176,177,178,179,180,181,182,183], poly(glycolic acid) (PGA) [184,185,186], poly(lactic acid) (PLA) [186,187,188,189,190,191,192,193,194,195], poly(lactic-co-glycolic acid) (PLGA) [42,168,186,187,188,196,197,198], poly(caprolactone) (PCL) [199,200,201,202,203,204,205,206], polyurethane (PU) [168], oligo(poly(ethylene glycol) fumarate) (OPF) [207], poly(ethylene terephthalate) (PET) [208,209,210,211,212], and hybrid compounds such as collagen/glycosaminoglycan (GAG) [213,214], collagen/silk [215,216,217], collagen/poly(desaminotyrosyl-tyrosine dodecyl dodecanedioate) (p(DTD DD)) [218], silk/PLGA [219], chitosan/HA [220], chitosan/PLA [221], chitosan/PCL [222], PLA/PCL [223], PGA/PCL [184], and PLA/PLGA systems [224], with successful attempts at material functionalization for ACL repair using for instance poly(sodium styrene sulfonate) (polyNaSS) grafting [205,206,209,211] (Table 1).
Such scaffolds have been further employed in conjunction with cells upon seeding onto biomaterials [2,42,43,45,46,47,49,54,56,59,60,62,64,67,68,69,70,213] such as differentiated fibroblasts and tissue (ACL, skin) [159,160,166,168,178,182,184,186,188,189,194,196,200,205,206,209,214,221,222] and progenitor cells (bone marrow-derived mesenchymal stromal cells—MSCs, adipose-derived MSCs—ASCs) [44,153,163,165,167,169,170,171,172,173,174,175,176,177,179,181,183,190,196,197,198,199,201,207,219,223,224], or even exosomes (extracellular vesicles carrying proteins, lipids, and nucleic acids and critical mediators of cell-cell communication) prepared from MSCs [230,231], tested in bioreactors to provide adaption to a dynamic environment with biomechanical cues to improve tissue repair [44,50,51,54,55,62,63,68,146,170,199,207] with further biological augmentation [8,45,47,48,49,54,56,60,65,68,70,155] including growth factors (TGF-β, basic FGF—FGF-2, growth differentiation factor 5—GDF-5, platelet-derived growth factor—PDGF, epidermal growth factor—EGF, connective tissue growth factor—CTGF, insulin) [151,154,172,198,199,203,219] and platelet-rich plasma (PRP, a derivative of whole blood with supraphysiological concentrations of platelets, with fibrin, and allowing for the release of growth factors and other bioactive substances and having inhibitory effects on inflammatory cytokines) [52,53,57,58,59,61,64,65,66,69,70,71,72,137,148,164,232,233,234,235] used as a hydrogel in combination with collagen [225,226,227,228,229] (Table 1).
While the use of biomaterial scaffolds with or without augmentation (cells, biological/mechanical stimuli) proved beneficial at least to a certain point experimentally, these systems have again been unable to support long-lasting ACL repair, showing the critical need for improved treatment strategies to effectively manage this clinical problem. In this regard, gene therapy may provide powerful tools to adeptly heal sites of ACL injury.

3. Classical Gene Therapy for the Repair of ACL Injuries

Gene therapy is based on the transfer of genetic sequences in target cells, tissues/organs, and live organisms with gene vehicles as a means to prolong the therapeutic effects of one or various gene products relative to the application of recombinant factors with short half-lives [73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,236,237]. Candidate factors for gene therapy may include growth and transcription factors, signaling molecules, as well as therapeutic RNAs that may be either suppressive (i.e., interfering) sequences such as oligodeoxyribonucleotide (ODNs), antisense RNAs, microRNAs (miRNAs), small interfering RNAs (siRNAs), short hairpin RNAs (shRNAs), and long non-coding RNAs (lncRNAs) or activating sequences such as messenger RNAs (mRNAs). Gene therapy can be performed either via a direct (in vivo) administration of the gene vector or via an indirect (ex vivo) supply of cells/grafts that are genetically modified in vitro prior to reimplantation in the recipient.

3.1. Gene Transfer Vectors

Gene vehicles include both nonviral and viral systems with specific characteristics that make them more adapted for in vivo or for ex vivo therapy (Table 2).
Nonviral vectors are non-replicative, non-immunogenic, safe systems without size limitation, but they exhibit a relatively low gene transfer efficiency for only very short periods of time (<40% for few weeks) since the genes being carried are kept as episomes that necessitate cell division for effective expression, making these vectors more suitable for ex vivo therapy [238,239].
Viral vectors that employ the ability of viruses to penetrate various cell types include adenoviral, herpes simplex viral (HSV), retro-l/lentiviral, and recombinant adeno-associated virus (rAAV) vectors. Adenoviral and HSV vectors are capable of directly modifying dividing and quiescent cells at elevated efficiencies (~100%), making them adapted for in vivo therapy, but they support only short-term (episomal) transgene expression (between some days to 1–2 weeks) while activating host immune responses [98,240,241,242]. Retroviral vectors have the ability to integrate in cellular genomes, allowing for long-term transgene expression, but they have low efficiencies (<20%), making them more suited for ex vivo therapy, and can only modify dividing cells, with possible insertional mutagenesis [243], while being also potentially immunogenic [98]. As an alternative, lentiviral vectors can also target quiescent cells, but they derive from the pathogenic human immunodeficiency virus (HIV) and may also lead to insertional mutagenesis [244]. rAAVs are small (~20 nm), safe vectors devoid of viral sequences and that are capable of modifying both dividing and quiescent cells at elevated efficiencies over extended periods of time (~100% for months to years) due their maintenance as stably expressed episomes [245,246], making them adapted for in vivo therapy, but they may raise immune responses, in particular by pre-existing neutralizing antibodies directed against the viral capsid proteins [98,247,248,249].

3.2. Candidate Therapeutic Factors

Therapeutic factors amenable to gene transfer to repair ACL injuries include growth factors, transcription factors, anti-inflammatory agents, matrix components, and signaling molecules.
A variety of polypeptide growth factors have been reported for their beneficial activities to repair ACL injuries. They include TGF-β [198,250,251,252,253,254,255,256,257,258], bone morphogenetic proteins (BMPs) and GDFs (BMP-2; GDF-5, i.e., BMP-14; GDF-6, i.e., BMP-13; GDF-7, i.e., BMP-12) [198,259,260,261,262], FGF-2 [251,255,256,262,263,264,265,266], insulin-like growth factors (IGF-I, IGF-II) [250,251,252,264], PDGF [251,252,256,258,260,264,265,267,268], EGF [251,252,254,265,269,270], hepatocyte growth factor (HGF) [260], CTGF [151], and vascular endothelial growth factor (VEGF) [271,272]. These factors play critical roles in stimulating cellular activities relevant for ACL repair such as cell migration and proliferation (TGF-β, GDFs, BMP-2, FGF-2, IGF-I, PDGF, EGF, HGF, CTGF, VEGF) [151,198,251,252,253,255,256,257,258,260,262,263,265,267,268,269,270,272], cell adhesion (GDFs, FGF-2, EGF) [262,269], matrix deposition (type-I/-III collagen, proteoglycans) (TGF-β, GDFs, FGF-2, IGF-I/-II, PDGF, EGF, CTGF) [151,198,250,252,254,255,256,258,259,261,262,266,268], angiogenesis (FGF-2, PDGF, VEGF) [266,268,271,272], and mechanical properties (stiffness) (TGF-β, FGF-2, IGF-I, PDGF, CTGF) [151,257,258,264,268].
Transcription factors have been also described for their advantageous properties for ACL repair [115,118,119,120,273], among which are SCX, regulating cell differentiation and matrix synthesis (type-I collagen, fibromodulin, tenomodulin—TNMD, decorin), especially in tendon progenitors [113,114,117,274,275,276,277,278,279], and MKX, essential for tendon/ligament differentiation by regulating the expression of matrix components (type-I collagen, fibromodulin, TNMD, decorin, lumican) [116,280,281,282,283].
Other components may be used as potential candidates for the repair of ACL lesions such as factors that may prevent the potential inflammation associated with injury [284,285,286,287,288,289,290,291,292,293,294,295] such as an anti-inflammatory IL-1 receptor antagonist (IL-1Ra) [295,296,297], soluble TNF-α receptor [296], IL-10 [298,299], or lysyl oxidase (LOX), an enzyme that oxidizes amino acid residues in collagens and elastin, allowing these compounds to bind to each other and to repair the extracellular matrix, and which can suppress inflammation in ACL cells [300]. Alternative candidates for ACL repair may also conceptually include matrix components such as collagens [301,302], TNMD [303,304,305,306], decorin [307,308,309], fibromodulin [310], biglycan [308,309], or others, as their presence is critical to the natural structure and functional integrity of the ACL. Other factors may also tentatively provide interesting candidates for ACL repair, such as those involved in signaling processes involved in ACL formation (wingless integrated—Wnt -/β-catenin, sonic hedgehog—SHH, FGF signaling via specific receptors, and ERK/MAPK, BMP/TGF-β/GDF signaling via specific receptors and Smads) [115,118,119,273,311,312].

3.3. Applications of Classical Gene Therapy for ACL Repair

Therapeutic gene therapy in the goal of ACL repair has been performed in relevant experimental models in cell culture in vitro, in tissue (explant) culture in situ, and in relevant animal models using both direct (in vivo) and indirect (ex vivo) gene transfer approaches.
In vitro and in situ (Table 3), the application of therapeutic genes has been reported using nonviral [313], adenoviral [282,314,315,316,317,318,319,320,321,322,323,324], retro-/lentiviral [275,283,314,315,325,326,327], and rAAV vectors [328].
These vectors were employed to deliver reporter genes (β-galactosidase—lacZ, green fluorescent protein—GFP, luciferase—luc) [313,314,315,317,318,328] and therapeutic sequences (TGF-β, BMP-2, BMP-12, BMP-13, FGF-2, IGF-I, PDGF, VEGF, SCX, MKX) [275,282,283,313,316,317,318,319,320,321,322,323,324,325,326,327,333] in rabbit, bovine, and human ACL cells and ACL explant (normal, experimentally torn) tissue [314,315,317,318,320,322,328] and in mouse, rat, rabbit, and human progenitor cells (MSCs, ACL-derived stem cells, perichondrial cells, induced pluripotent stem cells—iPSCs) [275,282,283,313,316,319,321,322,323,324,325,326,327,333]. Gene transfer allowed for an effective expression of the sequences being delivered for up to 2 days using nonviral vectors [313], one week using adenoviral vectors [282,314,315,316,317,318,319,320,321,323] or longer (2 weeks) if the modified cells where placed in hydrogel (type-I collagen) cultures [322], 12 weeks using retro-/lentiviral vectors upon cell selection [283,314,315,323,325,326,327,333], and at least one month using rAAV vectors [328]. Therapeutic gene transfer (TGF-β, BMP-12, BMP-13, FGF-2, IGF-I, VEGF) was capable of enhancing cell proliferation [317,318,320,322,328] using adenoviral vectors [317,318,320,322] for up to 2 weeks [317] and rAAV vectors for up to one month [328]. Therapeutic gene transfer (TGF-β, BMP-12, BMP-13, FGF-2, IGF-I, VEGF, SCX, MKX) also led to increased levels of matrix deposition and of specific marker expression (type-I/-III collagen, elastin, vimentin, fibromodulin, fibronectin—FN, tenascin, TNMD, decorin, lumican, biglycan, SCX, contractile alpha-smooth muscle actin—α-SMA) [275,282,283,317,318,320,322,324,327,328] using adenoviral vectors [282,317,318,320,324] for up to 3 weeks [283,317,322], retro-/lentiviral vectors over time upon cell selection [275,283,327], and rAAV vectors for up to one month [282]. Strikingly, rAAV-mediated gene delivery of FGF-2 over time (one month) was able to heal experimentally created human ACL lesions in situ via the enhanced expression of contractile α-SMA and of the ligament-specific SCX transcription factor and via increased collagen deposition [328]. Therapeutic RNAs have been also applied in vitro [329,330,334,335,336] and in situ [331], based on the delivery of ODNs (decorin, type V procollagen α1 chain) [329], miRNAs (Rho-associated coiled-coil protein kinase 1—ROCK1) [336], shRNAs (decorin) [335], lncRNAs (H19 lncRNA involved in TGF-β signaling) [334], and mRNAs (BMP-7) [331] using nonviral [329,330,331] and retro-/lentiviral vectors [334,335,336] to target rat, rabbit, and human ACL (and tendon) cells and explant tissue [329,330,331,335] and rat and human progenitor cells (tendon-derived stem cells) [334,336], allowing to suppress the expression of each specific marker while improving the ligamentous/tenogenic phenotype for up to one week [329,330,331,334,335,336].
Direct (in vivo) administration of therapeutic genes in animal models (Table 4) has been performed using nonviral [337,338,339] and adenoviral vectors [340,341,342] to deliver reporter genes (lacZ) [337,339,340,341] and therapeutic sequences (BMP-13, PDGF) [338,342] in experimentally created ligamentous lesions in rats [337,338,339,342] and in rabbits [340,341], allowing for the effective expression of the sequences being delivered for up to 2 weeks using nonviral vectors [337,339] and 6 weeks using adenoviral vectors at very high doses [340].
Therapeutic gene transfer (BMP-13, PDGF) was capable of enhancing type-I collagen deposition for 4 weeks in injured rat ligaments using nonviral vectors (PDGF) [338] and of promoting neoligament formation with increased levels of cell proliferation and collagen deposition for up to 14 weeks in a similar experimental model using adenoviral vectors (BMP-13) [342]. Therapeutic RNAs have been also directly applied in vivo [331,343,344,345], based on the delivery of ODNs (decorin) [343,345] and mRNAs (BMP-7, FGF-2) [331,344] using nonviral vectors [331,343,345] or only RNA solutions [344] in experimentally created ligamentous lesions in vivo in rats [331,344], in rabbits [343,345], and in sheep [331], allowing to suppress the expression of each specific marker while enhancing collagen deposition, mechanical stiffness, and healing for up to 6 weeks [331,343,344,345].
Indirect (ex vivo) application of therapeutic genes in animal models (Table 5) has been performed using nonviral [346], adenoviral [316,341,347,348], and retro-/lentiviral vectors [325,326,333,340] to deliver reporter genes (lacZ, GFP) [340,341,346,347] and therapeutic sequences (TGF-β, BMP-2, BMP-6, BMP-12, PDGF, VEGF) [316,325,333,346,347,348] as a means to modify rabbit ACL cells [340,341], rabbit and minipig ACL and tendon tissue grafts [346,347], and mouse, rat, rabbit, and human progenitor cells (MSCs, ACL-derived stem cells) [316,325,326,333,348] prior to applying them to ectopic models (muscle injection) in mice [316] or to experimentally created ligamentous lesions or for ACL replacement and repair in vivo in rats [325,326], in rabbits [333,340,341,347,348], and in minipigs [346], allowing for the effective expression of the sequences being delivered for up to 2 weeks using nonviral vectors [346] or adenoviral vectors [341,347] and 10 days using retro-/lentiviral vectors [340].
Therapeutic gene transfer (TGF-β, BMP-2, BMP-6, BMP-12, PDGF, VEGF) was capable of enhancing matrix deposition and specific marker expression (type-I/-III collagen, α-SMA) and promoting neoligament formation with increased levels of collagen deposition and improved mechanical properties in injured mouse, rat, rabbit, and minipig ligaments for up to 8 weeks using nonviral vectors (BMP-6) [346], 26 weeks using adenoviral vectors (TGF-β, BMP-2, BMP-12, VEGF) [316,347,348], and 12 weeks using retro-/lentiviral vectors (BMP-2, PDGF, VEGF) [325,326,333]. Therapeutic RNAs have been also indirectly applied in vivo [334,335], based on the delivery of shRNAs (decorin) [335] and lncRNAs (H19 lncRNA involved in TGF-β signaling) [334] using retro-/lentiviral vectors [334,335] as a means to modify rat tendon cells [335] and human progenitor cells (tendon-derived stem cells) [334] prior to applying them to experimentally created tendon lesions in vivo in mice [334] and in rats [335], allowing to enhance matrix deposition and specific marker expression (type-I collagen, TNMD, decorin) for up to 4 weeks [334,335].

3.4. Limitations of Classical Gene Therapy for ACL Repair

While experimental work showed the potential benefits of classical gene therapy for ACL repair, a number of critical limitations need to be carefully addressed before initiating relevant approaches for translational regenerative therapy in the field of clinically adapted repair in patients.
ACL gene therapy may be first hindered by pre-existing physical obstacles and biological barriers to effective and safe therapeutic gene transfer, including the presence of inhibitory factors in the joint (body fluids, i.e., synovial fluid; clinical compounds, i.e., heparin), the local pH and/or enzymatic environment, and the dense extracellular matrix of the tissue itself that may impair the penetration of the vectors before reaching the target cells [82,83,85,87,90,349]. Another impairment is associated with the existence of innate and/or adaptive responses from the immune system of the recipient (antibodies, cellular helper, and cytotoxic T cells) that may be directed against the viral particles and/or the transgene sequence (neutralization processes) [98,247,350,351,352,353]. Various cell-associated steps may also limit the rate and occurrence of therapeutic gene expression such as the effective uptake of the gene vector (presence/amount of the specific cell membrane receptor/co-receptor to a particular vector type), its successful internalization and transport in the cell (endosomal escape and nuclear entry), as well as its active processing (levels of adapted cell activity, transgenic genome conversion) [94,95,96,241,354,355,356]. Other challenges to address also involve inherent features of the vectors that may potentially affect the efficacy of the therapeutic treatment (vector dissemination to non-target sites in the joint, toxicity of viral vector proteins, genotoxicity upon a possible transgene integration in the host genome, transformation risk) [97].
A variety of strategies have been developed to tackle such issues, including (1) the use of alternative routes of vector injection, vector doses, clinical components (passive hirudin versus inhibitory heparin), immunosuppressive agents, and/or alternative (viral) vector serotypes, (2) the modification/masking of viral particles to evade host immune responses (chemical conjugation with polyethylene glycol—PEG, tropism/viral capsid tailoring by inclusion of substitute peptide sequences/epitopes, viral capsid engineering using chimeric/hybrid/mosaic/shuffled/variant/mutant/decoy vectors or virus-like particles—VLPs, vector-like microvesicles, vexosomes), and (3) the modification of the vector genome to circumvent the rate-limiting steps of its intracellular processing (tissue-specific/activatable/disease-responsive promoters, hybrid/self-complementary vectors, optimized coding/noncoding sequences in the transgene cassettes, artificial chromosomes) [82,83,85,87,90,96,245,357,358,359,360,361]. Still, even though such approaches led to some improvements in the efficacy of gene transfer, they remain complex (capsid/vector genome modification and engineering) or do not allow for sufficient and adapted therapeutic effects and outcomes, especially in vivo, while the variability of the host immune responses between patients has not been carefully taken into account with any of these techniques. Overall, these observations show the critical need to develop novel, suitable tools to address such challenges for clinical gene therapy, in particular for human ACL repair.

4. Biomaterial-Guided Gene Therapy for the Repair of ACL Injuries

The administration of therapeutic gene vectors using biomaterials already employed in tissue engineering research is an attractive approach to tackle the current obstacles of clinical human gene therapy and regenerative medicine [82,83,85,86,87,90,93,102,103,104,362,363] and might be applied in the goal of human ACL repair [90,91].

4.1. Principles

Biomaterial-guided gene therapy is a groundbreaking, convenient therapeutic concept based on the controlled delivery of gene transfer vectors from biocompatible scaffolds (hydrogels, solid scaffolds) originating from approaches developed to apply drugs and recombinant agents with such systems in human medicine [139,364,365,366,367,368,369]. Biomaterial-guided gene therapy instead combines the application of gene vehicles using materials (cargos) that may mimic the properties of the ACL tissue while strengthening it [99,100,101,370,371,372,373,374,375,376,377,378,379,380,381,382] in order to allow for a spatiotemporal, safe expression of therapeutic genetic sequences in the recipient via an off-the-shelf, cell-free (patient-independent) compound. Biomaterials may be derived from natural (biocompatible, biodegradable) or synthetic (reproducible) components, or both, to either encapsulate gene vectors to achieve a polymeric vector release (gradient release by degradation of the polymer loaded with the vectors during scaffold formation for hydrogels) or to immobilize the gene vectors to achieve a substrate-mediated release (release of the vectors incorporated at the surface of preformed scaffolds for solid scaffolds) [383]. Gene therapy guided via controlled release from biomaterials may allow for the stabilization of the gene vectors against degradation, to enhance the residence time of the therapeutic genes being carried and the effects of their products, to minimize vector dissemination to nontarget sites and the vector doses needed to be applied in patients, and to mask potentially immunogenic viral particle epitopes and protect the vectors from host immune responses [82,83,85,87,90,102].

4.2. Applications of Biomaterial-Guided Gene Therapy for ACL Repair

In vitro and in situ (Table 6), biomaterial-guided application of therapeutic genes has been reported using nonviral [384] and adenoviral vectors [317,318] delivered via type-I collagen hydrogels [317,318] and PLGA nanospheres [384]. These vectors were employed to transfer reporter genes (GFP) [317,318,384] and therapeutic sequences (TGF-β, IGF-I) [317,318] in bovine ACL cells [317], chicken tendon cells [384], and bovine and human ACL explant (experimentally torn) tissue [317,318].
Gene transfer allowed for an effective expression of the sequences being delivered for up to 3 weeks using nonviral vectors [384] and 4 weeks using adenoviral vectors [317,318]. Therapeutic gene transfer (TGF-β, IGF-I) was capable of enhancing cell proliferation using adenoviral vectors for up to 3 weeks [318] and the levels of matrix deposition (type-I/-III collagen) using adenoviral vectors for up to 4 weeks [317]. Strikingly, adenoviral-mediated gene delivery of TGF-β was further able to heal experimentally created bovine ACL lesions over a prolonged period of time (4 weeks) in situ [317]. Therapeutic RNAs have been also applied in vitro (Table 6) via delivery of miRNAs (TGF-β) using nonviral vectors delivered via PLGA nanospheres to target chicken tendon cells, allowing for the suppression of the expression of TGF-β for up to 3 weeks [384].
Biomaterial-guided application of therapeutic genes in animal models (Table 6) has been performed using nonviral [385], adenoviral [319], and rAAV vectors [387,388] to deliver reporter genes (luc) [388] and therapeutic sequences (TGF-β, GDF-5, BMP-12) [319,385,387,388] as a means to modify mouse [387,388] and rabbit tendon tissue grafts [385] and rat muscle tissue grafts [319] prior to applying them to experimentally created tendon and ligamentous lesions for tissue replacement and repair in vivo in mice [387,388], in rats [319], and in rabbits [385], allowing for the effective expression of the sequences being delivered for up to 3 weeks [387]. Therapeutic gene transfer (TGF-β, GDF-5, BMP-12) was capable of promoting wound healing with increased levels of collagen deposition and improved mechanical properties in injured mouse, rat, and rabbit tendons and ligaments for up to 6 months using nonviral vectors (TGF-β) [385], 4 weeks using adenoviral vectors (BMP-12) [319], and 3 weeks using rAAV vectors (GDF-5) [387,388]. Therapeutic RNAs have been also applied via biomaterials in animal models (Table 6) [335,384,386,389,390,391], based on the delivery of shRNAs (decorin) [335] and miRNAs (TGF-β, angiogenic miR-210) [384,386,389,390,391] using nonviral [384,386] and lentiviral vectors [335] or only as RNA solutions [389,390,391] delivered via rat tendon tissue grafts [335], type-I collagen hydrogels [389,390,391], PLGA nanospheres [384], and 3D-bioprinted composite (PCL, polydopamine—PDA—nanoparticles—NPs, gelatin, HA, alginate) scaffolds [386] in experimentally created tendon and ligamentous lesions for tissue replacement and repair in vivo in rats [335,389,390,391] and in chickens [384,386], allowing to suppress the expression of the specific marker (TGF-β) for up to 6 weeks [384] while enhancing matrix deposition and specific marker expression (type-I collagen, VEGF), mechanical stiffness, and healing for up to 12 weeks [335,384,386,389,390,391].

5. Conclusions

To address the unsolved problem of achieving long-lasting, safe, and mechanically competent ACL repair in patients, as none of the currently available clinical options (ACL reconstruction, engineering, augmentation) can competently afford it thus far, advanced strategies were developed to improve the intrinsic mechanisms of tissue repair in prevalent ACL injuries based on gene therapy procedures using durable therapeutic gene transfer (growth/transcription factors, anti-inflammatory agents, matrix components, signaling molecules, therapeutic RNAs) in vectors in experimental systems in vitro and in situ and relevant animal models in vivo via classical gene transfer methods (direct gene vector administration, indirect implantation of genetically modified cells and tissues). While such experimental approaches met undeniable success, they may be limited by the existence of physical and biological barriers in patients such as the joint environment (inhibitory soluble factors, dense extracellular matrix, immune host responses) and rate-limiting steps to effective therapeutic gene expression (ACL cell-associated rate-limiting steps, vector dissemination and toxicity). Besides active work using complex vector engineering techniques, a more convenient strategy, namely biomaterial-guided gene therapy, has emerged to tackle these issues via the application of biocompatible materials as cargos for therapeutic gene vectors, allowing for their spatiotemporal, safe, and prolonged controlled release and expression in the recipient while mimicking the properties of the ACL tissue and strengthening it. With promising results reported in experimental systems in vitro and in situ and in relevant animal models in vivo using this highly innovative procedure, work is now needed to confirm its workability in large preclinical animal models before envisaging a possible translation in individuals that first requires approval by regulatory organizations [83,392,393,394]. With this in mind, it still remains to be determined which biomaterial (type, production method possibly including three-dimensional—3D—bioprinting to mimic the structural features of the ACL) [395,396,397,398,399], vector (class, dose), and gene (single sequence or combination of genes, potential use of direct genome editing such as the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) system) [400,401,402,403,404,405,406,407,408,409] will be the most appropriate to effectively and permanently heal ACL lesions in order to be accessible to the patients in a near future.

Author Contributions

Conceptualization, M.A., V.M. and M.C.; writing—original draft preparation, M.A. and M.C.; writing—review and editing, M.A., J.K.V., W.L., A.L., T.N.N., H.M., V.M. and M.C.; supervision, M.C.; funding acquisition, V.M., H.M. and M.C. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the World Arthrosis Foundation (M.C. and H.M.) and as part of the “Future Investment Project” by the French Public Investment Bank and the French state—PSPC application—Liga2bio project (V.M.). We acknowledge support by the Saarland University within the funding program Open Access Publishing.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

References

  1. Kaeding, C.C.; Léger-St-Jean, B.; Magnussen, R.A. Epidemiology and Diagnosis of Anterior Cruciate Ligament Injuries. Clin. Sport. Med. 2016, 36, 1–8. [Google Scholar] [CrossRef] [PubMed]
  2. Kiapour, A.M.; Murray, M.M. Basic science of anterior cruciate ligament injury and repair. Bone Jt. Res. 2014, 3, 20–31. [Google Scholar] [CrossRef] [PubMed]
  3. Prodromos, C.C.; Han, Y.; Rogowski, J.; Joyce, B.; Shi, K. A Meta-analysis of the Incidence of Anterior Cruciate Ligament Tears as a Function of Gender, Sport, and a Knee Injury–Reduction Regimen. Arthrosc. J. Arthrosc. Relat. Surg. 2007, 23, 1320–1325.e6. [Google Scholar] [CrossRef] [PubMed]
  4. Fetto, J.F.; Marshall, J.L. The natural history and diagnosis of anterior cruciate ligament insufficiency. Clin. Orthop. Relat. Res. 1980, 147, 29–38. [Google Scholar] [CrossRef]
  5. Murray, M.M.; Martin, S.D.; Martin, T.L.; Spector, M. Histological Changes in the Human Anterior Cruciate Ligament After Rupture. J. Bone Jt. Surg. 2000, 82, 1387–1397. [Google Scholar] [CrossRef]
  6. Woo, S.L.-Y.; Vogrin, T.M.; Abramowitch, S.D. Healing and Repair of Ligament Injuries in the Knee. J. Am. Acad. Orthop. Surg. 2000, 8, 364–372. [Google Scholar] [CrossRef]
  7. Duthon, V.L.A.; Barea, C.; Abrassart, S.; Fasel, J.H.; Fritschy, D.; Menetrey, J. Anatomy of the anterior cruciate ligament. Knee Surg. Sport. Traumatol. Arthrosc. 2006, 14, 204–213. [Google Scholar] [CrossRef] [Green Version]
  8. Murray, M.M. Current Status and Potential of Primary ACL Repair. Clin. Sport. Med. 2009, 28, 51–61. [Google Scholar] [CrossRef] [Green Version]
  9. Jung, H.-J.; Fisher, M.B.; Woo, S.L.-Y. Role of biomechanics in the understanding of normal, injured, and healing ligaments and tendons. BMC Sport. Sci. Med. Rehabil. 2009, 1, 9–17. [Google Scholar] [CrossRef] [Green Version]
  10. Murray, M.M.; Fleming, B.C. Biology of anterior cruciate ligament injury and repair: Kappa delta ann doner vaughn award paper 2013. J. Orthop. Res. 2013, 31, 1501–1506. [Google Scholar] [CrossRef]
  11. Yang, G.; Rothrauff, B.B.; Tuan, R.S. Tendon and ligament regeneration and repair: Clinical relevance and developmental paradigm. Birth Defects Res. Part C Embryo Today Rev. 2013, 99, 203–222. [Google Scholar] [CrossRef] [Green Version]
  12. Kannus, P.; Jarvinen, M. Nonoperative treatment of acute knee ligament injuries. A review with special reference to indications and methods. Sports Med. 1990, 9, 244–260. [Google Scholar] [CrossRef]
  13. Jokl, P.; Kaplan, N.; Stovell, P.; Keggi, K. Non-operative treatment of severe injuries to the medial and anterior cruciate ligaments of the knee. J. Bone Jt. Surg. 1984, 66, 741–744. [Google Scholar] [CrossRef]
  14. Buss, D.D.; Min, R.; Skyhar, M.; Galinat, B.; Warren, R.F.; Wickiewicz, T.L. Nonoperative Treatment of Acute Anterior Cruciate Ligament Injuries in a Selected Group of Patients. Am. J. Sport. Med. 1995, 23, 160–165. [Google Scholar] [CrossRef]
  15. Ciccotti, M.G.; Lombardo, S.J.; Nonweiler, B.; Pink, M. Non-operative treatment of ruptures of the anterior cruciate ligament in middle-aged patients. Results after long-term follow-up. J. Bone Jt. Surg. 1994, 76, 1315–1321. [Google Scholar] [CrossRef]
  16. Maffulli, N. Rehabilitation of an anterior cruciate ligament. Clin. Orthop. Relat. Res. 1997, 343, 253–255. [Google Scholar] [CrossRef]
  17. Frank, C.B.; Jackson, D.W. Current Concepts Review—The Science of Reconstruction of the Anterior Cruciate Ligament. J. Bone Jt. Surg. 1997, 79, 1556–1576. [Google Scholar] [CrossRef]
  18. Fu, F.H.; Bennett, C.H.; Lattermann, C.; Ma, C.B. Current trends in anterior cruciate ligament reconstruction. Part I. Biology and biomechanics of reconstruction. Am. J. Sport. Med. 1999, 27, 821–830. [Google Scholar] [CrossRef]
  19. Fu, F.H.; Bennett, C.H.; Ma, C.B.; Menetrey, J.; Lattermann, C. Current trends in anterior cruciate ligament reconstruction. Part II. Operative procedures and clinical correlations. Am. J. Sport. Med. 2000, 28, 124–130. [Google Scholar] [CrossRef]
  20. Andersson, C.; Odensten, M.; Gillquist, J. Knee function after surgical or nonsurgical treatment of acute rupture of the anterior cruciate ligament: A randomized study with a long-term follow-up period. Clin. Orthop. Relat. Res. 1991, 264, 255–263. [Google Scholar] [CrossRef]
  21. Delincé, P.; Ghafil, D. Anterior cruciate ligament tears: Conservative or surgical treatment? A critical review of the literature. Knee Surg. Sport. Traumatol. Arthrosc. 2012, 20, 48–61. [Google Scholar] [CrossRef] [PubMed]
  22. Paschos, N.K.; Howell, S.M. Anterior cruciate ligament reconstruction: Principles of treatment. EFORT Open Rev. 2016, 1, 398–408. [Google Scholar] [CrossRef] [PubMed]
  23. Noyes, F.R.; Butler, D.L.; Grood, E.S.; Zernicke, R.F.; Hefzy, M.S. Biomechanical analysis of human ligament grafts used in knee-ligament repairs and reconstructions. J. Bone Jt. Surg. 1984, 66, 344–352. [Google Scholar] [CrossRef]
  24. Silver, F.H.; Tria, A.J.; Zawadsky, J.P.; Dunn, M. Anterior cruciate ligament replacement: A review. J. Long-Term Eff. Med. Implant. 1991, 1, 135–154. [Google Scholar]
  25. Chang, S.K.; Egami, D.K.; Shaieb, M.D.; Kan, D.M.; Richardson, A.B. Anterior cruciate ligament reconstruction: Allograft versus autograft. Arthrosc. J. Arthrosc. Relat. Surg. 2003, 19, 453–462. [Google Scholar] [CrossRef] [Green Version]
  26. Mascarenhas, R.; MacDonald, P.B. Anterior cruciate ligament reconstruction: A look at prosthetics--past, present and possible future. Mcgill. J. Med. 2008, 11, 29–37. [Google Scholar] [CrossRef]
  27. Chen, J.; Xu, J.; Wang, A.; Zheng, M. Scaffolds for tendon and ligament repair: Review of the efficacy of commercial products. Expert Rev. Med. Devices 2009, 6, 61–73. [Google Scholar] [CrossRef]
  28. Legnani, C.; Ventura, A.; Terzaghi, C.; Borgo, E.; Albisetti, W. Anterior cruciate ligament reconstruction with synthetic grafts. A review of literature. Int. Orthop. 2010, 34, 465–471. [Google Scholar] [CrossRef] [Green Version]
  29. Viateau, V.; Manassero, M.; Anagnostou, F.; Guérard, S.; Mitton, D.; Migonney, V. Biological and Biomechanical Evaluation of the Ligament Advanced Reinforcement System (LARS AC) in a Sheep Model of Anterior Cruciate Ligament Replacement: A 3-Month and 12-Month Study. Arthrosc. J. Arthrosc. Relat. Surg. 2013, 29, 1079–1088. [Google Scholar] [CrossRef] [Green Version]
  30. Ritchie, J.R.; Parker, R.D. Graft Selection in Anterior Cruciate Ligament Revision Surgery. Clin. Orthop. Relat. Res. 1996, 325, 65–77. [Google Scholar] [CrossRef]
  31. Aglietti, P.; Buzzi, R.; Giron, F.; Simeone, A.J.V.; Zaccherotti, G. Arthroscopic-assisted anterior cruciate ligament reconstruction with the central third patellar tendon. Knee Surg. Sport. Traumatol. Arthrosc. 1997, 5, 138–144. [Google Scholar] [CrossRef]
  32. Bach, B.R.; Tradonsky, S.; Bojchuk, J.; Levy, M.E.; Bush-Joseph, C.A.; Khan, N.H. Arthroscopically Assisted Anterior Cruciate Ligament Reconstruction Using Patellar Tendon Autograft. Am. J. Sport. Med. 1998, 26, 20–29. [Google Scholar] [CrossRef]
  33. Jomha, N.M.; Borton, D.C.; Clingeleffer, A.J.; Pinczewski, L. Long Term Osteoarthritic Changes in Anterior Cruciate Ligament Reconstructed Knees. Clin. Orthop. Relat. Res. 1999, 358, 188–193. [Google Scholar] [CrossRef]
  34. Jomha, N.M.; A Pinczewski, L.; Clingeleffer, A.; Otto, D.D. Arthroscopic reconstruction of the anterior cruciate ligament with patellar-tendon autograft and interference screw fixation. The results at seven years. J. Bone Jt. Surg. Br. 1999, 81, 775–779. [Google Scholar] [CrossRef]
  35. Segawa, H.; Omori, G.; Koga, Y. Long-term results of non-operative treatment of anterior cruciate ligament injury. Knee 2001, 8, 5–11. [Google Scholar] [CrossRef]
  36. Anderson, A.F.; Snyder, R.B.; Lipscomb, A.B., Jr. Anterior cruciate ligament reconstruction. A prospective randomized study of three surgical methods. Am. J. Sports Med. 2001, 29, 272–279. [Google Scholar] [CrossRef]
  37. Weitzel, P.P.; Richmond, J.C.; Altman, G.H.; Calabro, T.; Kaplan, D.L. Future direction of the treatment of ACL ruptures. Orthop. Clin. N. Am. 2002, 33, 653–661. [Google Scholar] [CrossRef]
  38. Von Porat, A.; Roos, E.; Roos, H. High prevalence of osteoarthritis 14 years after an anterior cruciate ligament tear in male soccer players: A study of radiographic and patient relevant outcomes. Ann. Rheum. Dis. 2004, 63, 269–273. [Google Scholar] [CrossRef]
  39. Kaeding, C.C.; Aros, B.; Pedroza, A.; Pifel, E.; Amendola, A.; Andrish, J.T.; Dunn, W.R.; Marx, R.G.; McCarty, E.C.; Parker, R.D.; et al. Allograft versus autograft anterior cruciate ligament reconstruction: Predictors of failure from a MOON prospective longitudinal cohort. Sports Health 2011, 3, 73–81. [Google Scholar] [CrossRef] [Green Version]
  40. Paterno, M.V.; Rauh, M.J.; Schmitt, L.C.; Ford, K.; Hewett, T.E. Incidence of Second ACL Injuries 2 Years After Primary ACL Reconstruction and Return to Sport. Am. J. Sport. Med. 2014, 42, 1567–1573. [Google Scholar] [CrossRef] [Green Version]
  41. Ahmed, I.; Salmon, L.; Roe, J.; Pinczewski, L. The long-term clinical and radiological outcomes in patients who suffer recurrent injuries to the anterior cruciate ligament after reconstruction. Bone Jt. J. 2017, 99-B, 337–343. [Google Scholar] [CrossRef]
  42. Laurencin, C.; Attawia, M.; Botchwey, E.; Warren, R.; Attia, E. Cell-material systems for anterior cruciate ligament regeneration. In Vitro Cell Dev. Biol. Anim. 1998, 34, 90–92. [Google Scholar] [CrossRef]
  43. Laurencin, C.T.; Ambrosio, A.M.A.; Borden, M.D.; Cooper, J.A. Tissue Engineering: Orthopedic Applications. Annu. Rev. Biomed. Eng. 1999, 1, 19–46. [Google Scholar] [CrossRef]
  44. Altman, G.H.; Horan, R.L.; Martin, I.; Farhadi, J.; Stark, P.R.H.; Volloch, V.; Richmond, J.C.; Vunjak-Novakovic, G.; Kaplan, D.L. Cell differentiation by mechanical stress. FASEB J. 2002, 16, 270–272. [Google Scholar] [CrossRef] [Green Version]
  45. Vunjak-Novakovic, G.; Altman, G.; Horan, R.; Kaplan, D.L. Tissue Engineering of Ligaments. Annu. Rev. Biomed. Eng. 2004, 6, 131–156. [Google Scholar] [CrossRef]
  46. Laurencin, C.T.; Freeman, J.W. Ligament tissue engineering: An evolutionary materials science approach. Biomaterials 2005, 26, 7530–7536. [Google Scholar] [CrossRef]
  47. Petrigliano, F.A.; McAllister, D.R.; Wu, B.M. Tissue Engineering for Anterior Cruciate Ligament Reconstruction: A Review of Current Strategies. Arthrosc. J. Arthrosc. Relat. Surg. 2006, 22, 441–451. [Google Scholar] [CrossRef] [PubMed]
  48. Angel, M.J.; Sgaglione, N.A.; Grande, D.A. Clinical applications of bioactive factors in sports medicine: Current concepts and future trends. Sports Med. Arthrosc. Rev. 2006, 14, 138–145. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  49. Woo, S.L.Y.; Fisher, M.B.; Feola, A. Contribution of biomechanics to management of ligament and tendon injuries. Mol. Cell Biomech. 2008, 5, 49–68. [Google Scholar] [PubMed]
  50. Kahn, C.J.; Vaquette, C.; Rahouadj, R.; Wang, X. A novel bioreactor for ligament tissue engineering. Biomed. Mater. Eng. 2008, 18, 283–287. [Google Scholar] [CrossRef] [PubMed]
  51. Benhardt, H.A.; Cosgriff-Hernandez, E.M. The Role of Mechanical Loading in Ligament Tissue Engineering. Tissue Eng. Part B Rev. 2009, 15, 467–475. [Google Scholar] [CrossRef]
  52. Hall, M.P.; Band, P.A.; Meislin, R.J.; Jazrawi, L.M.; Cardone, D.A. Platelet-rich Plasma: Current Concepts and Application in Sports Medicine. J. Am. Acad. Orthop. Surg. 2009, 17, 602–608. [Google Scholar] [CrossRef] [Green Version]
  53. Taylor, D.W.; Petrera, M.; Hendry, M.; Theodoropoulos, J. A Systematic Review of the Use of Platelet-Rich Plasma in Sports Medicine as a New Treatment for Tendon and Ligament Injuries. Clin. J. Sport Med. 2011, 21, 344–352. [Google Scholar] [CrossRef] [Green Version]
  54. Rodrigues, M.T.; Reis, R.L.; Gomes, M.E. Engineering tendon and ligament tissues: Present developments towards successful clinical products. J. Tissue Eng. Regen. Med. 2013, 7, 673–686. [Google Scholar] [CrossRef] [Green Version]
  55. Wang, T.; Gardiner, B.S.; Lin, Z.; Rubenson, J.; Kirk, T.B.; Wang, A.; Xu, J.; Smith, D.W.; Lloyd, D.G.; Zheng, M.H. Bioreactor Design for Tendon/Ligament Engineering. Tissue Eng. Part B Rev. 2013, 19, 133–146. [Google Scholar] [CrossRef] [Green Version]
  56. Leong, N.L.; Petrigliano, F.A.; McAllister, D.R. Current tissue engineering strategies in anterior cruciate ligament reconstruction. J. Biomed. Mater. Res. Part A 2014, 102, 1614–1624. [Google Scholar] [CrossRef]
  57. Yuan, T.; Zhang, C.-Q.; Wang, J.H.-C. Augmenting tendon and ligament repair with platelet-rich plasma (PRP). Muscle Ligaments Tendons J. 2013, 3, 139–149. [Google Scholar] [CrossRef] [Green Version]
  58. Moraes, V.Y.; Lenza, M.; Tamaoki, M.J.S.; Faloppa, F.; Belloti, J.C. Platelet-rich therapies for musculoskeletal soft tissue injuries. Cochrane Database Syst. Rev. 2014, 2014, CD010071. [Google Scholar] [CrossRef]
  59. Hogan, M.; Kawakami, Y.; Murawski, C.D.; Fu, F.H. Tissue Engineering of Ligaments for Reconstructive Surgery. Arthrosc. J. Arthrosc. Relat. Surg. 2015, 31, 971–979. [Google Scholar] [CrossRef]
  60. Nau, T.; Teuschl, A. Regeneration of the anterior cruciate ligament: Current strategies in tissue engineering. World J. Orthop. 2015, 6, 127–136. [Google Scholar] [CrossRef] [Green Version]
  61. Andriolo, L.; Di Matteo, B.; Kon, E.; Filardo, G.; Venieri, G.; Marcacci, M. PRP Augmentation for ACL Reconstruction. BioMed Res. Int. 2015, 2015, 371746. [Google Scholar] [CrossRef] [PubMed]
  62. Mace, J.; Wheelton, A.; Khan, W.S.; Anand, S. The Role of Bioreactors in Ligament and Tendon Tissue Engineering. Curr. Stem Cell Res. Ther. 2016, 11, 35–40. [Google Scholar] [CrossRef] [PubMed]
  63. Negahi Shirazi, A.; Chrzanowski, W.; Khademhosseini, A.; Dehghani, F. Anterior cruciate ligament structure, injuries and regenerative treatments. Adv. Exp. Med. Biol. 2015, 881, 161–186. [Google Scholar] [PubMed]
  64. Hexter, A.T.; Thangarajah, T.; Blunn, G.; Haddad, F.S. Biological augmentation of graft healing in anterior cruciate ligament reconstruction: A systematic review. Bone Jt. J. 2018, 100-B, 271–284. [Google Scholar] [CrossRef] [PubMed]
  65. Chahla, J.; Kennedy, M.I.; Aman, Z.S.; LaPrade, R.F. Ortho-Biologics for Ligament Repair and Reconstruction. Clin. Sport. Med. 2019, 38, 97–107. [Google Scholar] [CrossRef]
  66. Riediger, M.D.; Stride, D.; Coke, S.E.; Kurz, A.Z.; Duong, A.; Ayeni, O.R. ACL Reconstruction with Augmentation: A Scoping Review. Curr. Rev. Musculoskelet. Med. 2019, 12, 166–172. [Google Scholar] [CrossRef]
  67. Hevesi, M.; LaPrade, M.; Saris, D.B.F.; Krych, A.J. Stem Cell Treatment for Ligament Repair and Reconstruction. Curr. Rev. Musculoskelet. Med. 2019, 12, 446–450. [Google Scholar] [CrossRef]
  68. Lim, W.L.; Liau, L.L.; Ng, M.H.; Chowdhury, S.R.; Law, J.X. Current Progress in Tendon and Ligament Tissue Engineering. Tissue Eng. Regen. Med. 2019, 16, 549–571. [Google Scholar] [CrossRef]
  69. Uchida, R.; Jacob, G.; Shimomura, K.; Horibe, S.; Nakamura, N. Biological Augmentation of ACL Repair and Reconstruction: Current Status and Future Perspective. Sport. Med. Arthrosc. Rev. 2020, 28, 49–55. [Google Scholar] [CrossRef]
  70. Looney, A.M.; Leider, J.D.; Horn, A.R.; Bodendorfer, B.M. Bioaugmentation in the surgical treatment of anterior cruciate ligament injuries: A review of current concepts and emerging techniques. SAGE Open Med. 2020, 8, 2050312120921057. [Google Scholar] [CrossRef]
  71. Kon, E.; Di Matteo, B.; Altomare, D.; Iacono, F.; Kurpyakov, A.; Lychagin, A.; Timashev, P.; Kalinsky, E.; Lipina, M. Biologic agents to optimize outcomes following ACL repair and reconstruction: A systematic review of clinical evidence. J. Orthop. Res. 2022, 40, 10–28. [Google Scholar] [CrossRef]
  72. Su, C.A.; Jildeh, T.R.; Vopat, M.L.; Waltz, R.A.; Millett, P.J.; Provencher, M.T.; Philippon, M.J.; Huard, J. Current State of Platelet-Rich Plasma and Cell-Based Therapies for the Treatment of Osteoarthritis and Tendon and Ligament Injuries. J. Bone Jt. Surg. 2022, 104, 1406–1414. [Google Scholar] [CrossRef]
  73. Gerich, T.G.; Fu, F.H.; Robbins, P.D.; Evans, C.H. Prospects for gene therapy in sports medicine. Knee Surg. Sport. Traumatol. Arthrosc. 1996, 4, 180–187. [Google Scholar] [CrossRef]
  74. Evans, C.H.; Ghivizzani, S.C.; Robbins, P.D. Potential Applications of Gene Therapy in Sports Medicine. Phys. Med. Rehabil. Clin. North Am. 2000, 11, 405–416. [Google Scholar] [CrossRef]
  75. Wu, D.; Razzano, P.; Grande, D.A. Gene therapy and tissue engineering in repair of the musculoskeletal system. J. Cell. Biochem. 2003, 88, 467–481. [Google Scholar] [CrossRef]
  76. Huard, J.; Li, Y.; Peng, H.; Fu, F.H. Gene therapy and tissue engineering for sports medicine. J. Gene Med. 2003, 5, 93–108. [Google Scholar] [CrossRef]
  77. Hildebrand, K.; Frank, C.; Hart, D. Gene intervention in ligament and tendon: Current status, challenges, future directions. Gene Ther. 2004, 11, 368–378. [Google Scholar] [CrossRef] [Green Version]
  78. A Eming, S.; Krieg, T.; Davidson, J.M. Gene transfer in tissue repair: Status, challenges and future directions. Expert Opin. Biol. Ther. 2004, 4, 1373–1386. [Google Scholar] [CrossRef]
  79. Kofron, M.D.; Laurencin, C.T. Orthopaedic applications of gene therapy. Curr. Gene Ther. 2005, 5, 37–61. [Google Scholar] [CrossRef]
  80. Nixon, A.J.; Goodrich, L.R.; Scimeca, M.S.; Witte, T.; Schnabel, L.V.; Watts, A.E.; Robbins, P.D. Gene Therapy in Musculoskeletal Repair. Ann. N. Y. Acad. Sci. 2007, 1117, 310–327. [Google Scholar] [CrossRef]
  81. Docheva, D.; Müller, S.A.; Majewski, M.; Evans, C.H. Biologics for tendon repair. Adv. Drug Deliv. Rev. 2015, 84, 222–239. [Google Scholar] [CrossRef] [PubMed]
  82. Rey-Rico, A.; Cucchiarini, M. Controlled release strategies for rAAV-mediated gene delivery. Acta Biomater. 2016, 29, 1–10. [Google Scholar] [CrossRef] [PubMed]
  83. Cucchiarini, M. Human gene therapy: Novel approaches to improve the current gene delivery systems. Discov. Med. 2016, 21, 495–506. [Google Scholar] [PubMed]
  84. Dunbar, C.E.; High, K.A.; Joung, J.K.; Kohn, D.B.; Ozawa, K.; Sadelain, M. Gene therapy comes of age. Science 2018, 359, eaan4672. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Venkatesan, J.K.; Falentin-Daudré, C.; Leroux, A.; Migonney, V.; Cucchiarini, M. Controlled release of gene therapy constructs from solid scaffolds for therapeutic applications in orthopedics. Discov. Med. 2018, 25, 195–203. [Google Scholar] [PubMed]
  86. Balmayor, E.R.; Evans, C.H. RNA Therapeutics for Tissue Engineering. Tissue Eng. Part A 2019, 25, 9–11. [Google Scholar] [CrossRef]
  87. Cucchiarini, M.; Madry, H. Biomaterial-guided delivery of gene vectors for targeted articular cartilage repair. Nat. Rev. Rheumatol. 2019, 15, 18–29. [Google Scholar] [CrossRef]
  88. Evans, C.; De la Vega, R.E.; Evans, C.H.; van Griensven, M.; Balmayor, E.R. Healing with RNA. Injury 2019, 50, 625–626. [Google Scholar] [CrossRef]
  89. High, K.A.; Roncarolo, M.G. Gene therapy. N. Engl. J. Med. 2019, 381, 455–464. [Google Scholar] [CrossRef]
  90. Venkatesan, J.K.; Rey-Rico, A.; Cucchiarini, M. Current Trends in Viral Gene Therapy for Human Orthopaedic Regenerative Medicine. Tissue Eng. Regen. Med. 2019, 16, 345–355. [Google Scholar] [CrossRef]
  91. Giordano, L.; Della Porta, G.; Peretti, G.M.; Maffulli, N. Therapeutic potential of microRNA in tendon injuries. Br. Med. Bull. 2020, 133, 79–94. [Google Scholar] [CrossRef]
  92. Evans, C.H.; Ghivizzani, S.C.; Robbins, P.D. Orthopaedic gene therapy: Twenty-five years on. JBJS Rev. 2021, 9, e20. [Google Scholar] [CrossRef]
  93. Balmayor, E.R. Synthetic mRNA—Emerging new class of drug for tissue regeneration. Curr. Opin. Biotechnol. 2022, 74, 8–14. [Google Scholar] [CrossRef]
  94. Lechardeur, D.; Lukacs, G.L. Intracellular barriers to non-viral gene transfer. Curr. Gene Ther. 2002, 2, 183–194. [Google Scholar] [CrossRef]
  95. Huang, H.-Y.; Huang, Y.-Y. Intracellular Trafficking, Metabolism and Toxicity of Current Gene Carriers. Curr. Drug Metab. 2009, 10, 885–894. [Google Scholar]
  96. Kay, M.A. State-of-the-art gene-based therapies: The road ahead. Nat. Rev. Genet. 2011, 12, 316–328. [Google Scholar] [CrossRef]
  97. Kaufmann, K.B.; Büning, H.; Galy, A.; Schambach, A.; Grez, M. Gene therapy on the move. EMBO Mol. Med. 2013, 5, 1642–1661. [Google Scholar] [CrossRef]
  98. Shirley, J.L.; de Jong, Y.P.; Terhorst, C.; Herzog, R.W. Immune Responses to Viral Gene Therapy Vectors. Mol. Ther. 2020, 28, 709–722. [Google Scholar] [CrossRef]
  99. Shea, L.D.; Smiley, E.; Bonadio, J.; Mooney, D.J. DNA delivery from polymer matrices for tissue engineering. Nat. Biotechnol. 1999, 17, 551–554. [Google Scholar] [CrossRef]
  100. Pannier, A.K.; Shea, L.D. Controlled release systems for DNA delivery. Mol. Ther. 2004, 10, 19–26. [Google Scholar] [CrossRef]
  101. Jang, J.-H.; Schaffer, D.V.; Shea, L.D. Engineering Biomaterial Systems to Enhance Viral Vector Gene Delivery. Mol. Ther. 2011, 19, 1407–1415. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. Raftery, R.; Walsh, D.; Castaño, I.M.; Heise, A.; Duffy, G.; Cryan, S.-A.; O’Brien, F.J. Delivering Nucleic-Acid Based Nanomedicines on Biomaterial Scaffolds for Orthopedic Tissue Repair: Challenges, Progress and Future Perspectives. Adv. Mater. 2016, 28, 5447–5469. [Google Scholar] [CrossRef] [PubMed]
  103. Curtin, C.; Castaño, I.M.; O’Brien, F.J. Scaffold-Based microRNA Therapies in Regenerative Medicine and Cancer. Adv. Health Mater. 2018, 7, 1700695. [Google Scholar] [CrossRef]
  104. Kelly, D.C.; Raftery, R.M.; Curtin, C.M.; O’Driscoll, C.M.; O’Brien, F.J. Scaffold-Based Delivery of Nucleic Acid Therapeutics for Enhanced Bone and Cartilage Repair. J. Orthop. Res. 2019, 37, 1671–1680. [Google Scholar] [CrossRef] [PubMed]
  105. Arnoczky, S.P. Anatomy of the anterior cruciate ligament. Clin. Orthop. Relat. Res. 1983, 172, 19–25. [Google Scholar] [CrossRef]
  106. Sakane, M.; Fox, R.J.; Glen, S.L.-Y.W.; Livesay, A.; Li, G.; Fu, F.H. In situ forces in the anterior cruciate ligament and its bundles in response to anterior tibial loads. J. Orthop. Res. 1997, 15, 285–293. [Google Scholar] [CrossRef]
  107. Beynnon, B.D.; Johnson, R.J.; Fleming, B.C.; Peura, G.D.; Renstrom, P.A.; Nichols, C.E.; Pope, M.H. The Effect of Functional Knee Bracing on the Anterior Cruciate Ligament in the Weightbearing and Nonweightbearing Knee. Am. J. Sport. Med. 1997, 25, 353–359. [Google Scholar] [CrossRef]
  108. Noyes, F.R.; Grood, E.S. The strength of the anterior cruciate ligament in humans and Rhesus monkeys. J. Bone Jt. Surg. 1976, 58, 1074–1082. [Google Scholar] [CrossRef]
  109. Guarino, V.; Causa, F.; Ambrosio, L. Bioactive scaffolds for bone and ligament tissue. Expert Rev. Med. Devices 2007, 4, 405–418. [Google Scholar] [CrossRef]
  110. Gomez-Rodriguez, J.; Readinger, J.A.; Viorritto, I.C.; Mueller, K.L.; Houghtling, R.A.; Schwartzberg, P.L. Tec kinases, actin, and cell adhesion. Immunol. Rev. 2007, 218, 45–64. [Google Scholar] [CrossRef]
  111. Dourte, L.M.; Kuntz, A.F.; Soslowsky, L.J. Twenty-five years of tendon and ligament research. J. Orthop. Res. 2008, 26, 1297–1305. [Google Scholar] [CrossRef]
  112. Connizzo, B.K.; Yannascoli, S.M.; Soslowsky, L.J. Structure–function relationships of postnatal tendon development: A parallel to healing. Matrix Biol. 2013, 32, 106–116. [Google Scholar] [CrossRef]
  113. Cserjesi, P.; Brown, D.; Ligon, K.L.; E Lyons, G.; Copeland, N.G.; Gilbert, D.J.; A Jenkins, N.; Olson, E.N. Scleraxis: A basic helix-loop-helix protein that prefigures skeletal formation during mouse embryogenesis. Development 1995, 121, 1099–1110. [Google Scholar] [CrossRef]
  114. Schweitzer, R.; Chyung, J.H.; Murtaugh, L.C.; E Brent, A.; Rosen, V.; Olson, E.N.; Lassar, A.; Tabin, C.J. Analysis of the tendon cell fate using Scleraxis, a specific marker for tendons and ligaments. Development 2001, 128, 3855–3866. [Google Scholar] [CrossRef]
  115. Tozer, S.; Duprez, D. Tendon and ligament: Development, repair and disease. Birth Defects Res. C Embryo. Today 2005, 75, 226–236. [Google Scholar] [CrossRef]
  116. Anderson, D.M.; Arredondo, J.; Hahn, K.; Valente, G.; Martin, J.F.; Wilson-Rawls, J.; Rawls, A. Mohawk is a novel homeobox gene expressed in the developing mouse embryo. Dev. Dyn. 2006, 235, 792–801. [Google Scholar] [CrossRef]
  117. Shukunami, C.; Takimoto, A.; Oro, M.; Hiraki, Y. Scleraxis positively regulates the expression of tenomodulin, a differentiation marker of tenocytes. Dev. Biol. 2006, 298, 234–247. [Google Scholar] [CrossRef] [Green Version]
  118. Liu, H.; Zhu, S.; Zhang, C.; Lu, P.; Hu, J.; Yin, Z.; Ma, Y.; Chen, X.; OuYang, H. Crucial transcription factors in tendon development and differentiation: Their potential for tendon regeneration. Cell Tissue Res. 2014, 356, 287–298. [Google Scholar] [CrossRef]
  119. Asahara, H.; Inui, M.; Lotz, M.K. Tendons and Ligaments: Connecting Developmental Biology to Musculoskeletal Disease Pathogenesis. J. Bone Miner. Res. 2017, 32, 1773–1782. [Google Scholar] [CrossRef] [Green Version]
  120. Bobzin, L.; Roberts, R.R.; Chen, H.-J.; Crump, J.G.; Merrill, A.E. Development and maintenance of tendons and ligaments. Development 2021, 148, dev186916. [Google Scholar] [CrossRef]
  121. Zantop, T.; Petersen, W.; Sekiya, J.K.; Musahl, V.; Fu, F.H. Anterior cruciate ligament anatomy and function relating to anatomical reconstruction. Knee Surg. Sport. Traumatol. Arthrosc. 2006, 14, 982–992. [Google Scholar] [CrossRef] [PubMed]
  122. Lessim, S.; Migonney, V.; Thoreux, P.; Lutomski, D.; Changotade, S. PolyNaSS bioactivation of LARS artificial ligament promotes human ligament fibroblast colonisation in vitro. Bio-Med. Mater. Eng. 2013, 23, 289–297. [Google Scholar] [CrossRef] [PubMed]
  123. Brodsky, J.W.; Schneidler, C. Diabetic foot infections. Orthop. Clin. N. Am. 1991, 22, 473–489. [Google Scholar] [CrossRef]
  124. Carpenter, J.E.; Thomopoulos, S.; Soslowsky, L.J. Animal Models of Tendon and Ligament Injuries for Tissue Engineering Applications. Clin. Orthop. Relat. Res. 1999, 367, S296–S311. [Google Scholar] [CrossRef] [PubMed]
  125. Woo, S.L.-Y.; Hildebrand, K.; Watanabe, N.; Fenwick, J.A.; Papageorgiou, C.D.; Wang, J.H.-C. Tissue Engineering of Ligament and Tendon Healing. Clin. Orthop. Relat. Res. 1999, 367, S312–S323. [Google Scholar] [CrossRef] [PubMed]
  126. Goh, J.C.-H.; Ouyang, H.-W.; Teoh, S.-H.; Chan, C.K.; Lee, E.-H. Tissue-Engineering Approach to the Repair and Regeneration of Tendons and Ligaments. Tissue Eng. 2003, 9, 31–44. [Google Scholar] [CrossRef]
  127. Laurencin, C.T.; Khan, Y.; Kofron, M.; El-Amin, S.; Botchwey, E.; Yu, X.; Cooper, J.A., Jr. The ABJS Nicolas Andry Award: Tissue engineering of bone and ligament: A 15-year perspective. Clin. Orthop. Relat. Res. 2006, 447, 221–236. [Google Scholar]
  128. Doroski, D.M.; Brink, K.S.; Temenoff, J.S. Techniques for biological characterization of tissue-engineered tendon and ligament. Biomaterials 2007, 28, 187–202. [Google Scholar] [CrossRef]
  129. Freed, L.E.; Guilak, F.; Guo, X.E.; Gray, M.L.; Tranquillo, R.; Holmes, J.W.; Radisic, M.; Sefton, M.V.; Kaplan, D.; Vunjak-Novakovic, G. Advanced Tools for Tissue Engineering: Scaffolds, Bioreactors, and Signaling. Tissue Eng. 2006, 12, 3285–3305. [Google Scholar] [CrossRef]
  130. Mikos, A.G.; Herring, S.W.; Ochareon, P.; Elisseeff, J.; Lu, H.H.; Kandel, R.; Schoen, F.J.; Toner, M.; Mooney, D.; Atala, A.; et al. Engineering Complex Tissues. Tissue Eng. 2006, 12, 3307–3339. [Google Scholar] [CrossRef]
  131. Altman, G.H.; Horan, R.L.; Weitzel, P.; Richmond, J.C. The Use of Long-term Bioresorbable Scaffolds for Anterior Cruciate Ligament Repair. J. Am. Acad. Orthop. Surg. 2008, 16, 177–187. [Google Scholar] [CrossRef]
  132. Vieira, A.; Guedes, R.; Marques, A. Development of ligament tissue biodegradable devices: A review. J. Biomech. 2009, 42, 2421–2430. [Google Scholar] [CrossRef] [Green Version]
  133. Vavken, P.; Murray, M.M. Translational studies in anterior cruciate ligament repair. Tissue Eng. Part B Rev. 2010, 16, 5–11. [Google Scholar] [CrossRef]
  134. Silva, S.S.; Mano, J.F.; Reis, R.L. Potential applications of natural origin polymer-based systems in soft tissue regeneration. Crit. Rev. Biotechnol. 2010, 30, 200–221. [Google Scholar] [CrossRef] [Green Version]
  135. Atala, A.; Kasper, F.K.; Mikos, A.G. Engineering Complex Tissues. Sci. Transl. Med. 2012, 4, 160rv12. [Google Scholar] [CrossRef] [Green Version]
  136. Muller, B.; Bowman, K.F.; Bedi, A. ACL Graft Healing and Biologics. Clin. Sport. Med. 2013, 32, 93–109. [Google Scholar] [CrossRef]
  137. Middleton, K.K.; Barro, V.; Muller, B.; Terada, S.; Fu, F.H. 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. [Google Scholar]
  138. Hutchinson, I.D.; Rodeo, S.A.; Perrone, G.S.; Murray, M.M. Can platelet-rich plasma enhance anterior cruciate ligament and meniscal repair? J. Knee Surg. 2015, 28, 19–28. [Google Scholar] [CrossRef] [Green Version]
  139. Teh, T.K.H.; Goh, J.C.H.; Toh, S.L. Controlled Bioactive Molecules Delivery Strategies for Tendon and Ligament Tissue Engineering using Polymeric Nanofibers. Curr. Pharm. Des. 2015, 21, 1991–2005. [Google Scholar] [CrossRef]
  140. Mengsteab, P.Y.; Nair, L.S.; Laurencin, C.T. The past, present and future of ligament regenerative engineering. Regen. Med. 2016, 11, 871–881. [Google Scholar] [CrossRef] [Green Version]
  141. Cengiz, I.F.; Pereira, H.; De Girolamo, L.; Cucchiarini, M.; Espregueira-Mendes, J.; Reis, R.L.; Oliveira, J.M. Orthopaedic regenerative tissue engineering en route to the holy grail: Disequilibrium between the demand and the supply in the operating room. J. Exp. Orthop. 2018, 5, 14. [Google Scholar] [CrossRef] [PubMed]
  142. Mahapatra, P.; Horriat, S.; Anand, B.S. Anterior cruciate ligament repair—Past, present and future. J. Exp. Orthop. 2018, 5, 20. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  143. Cengiz, I.F.; Pereira, H.; Espregueira-Mendes, J.; Reis, R.L.; Oliveira, J.M. The clinical use of biologics in the knee lesions: Does the patient benefit? Curr. Rev. Musculoskelet. Med. 2019, 12, 406–414. [Google Scholar] [CrossRef] [PubMed]
  144. No, Y.J.; Castilho, M.; Ramaswamy, Y.; Zreiqat, H. Role of Biomaterials and Controlled Architecture on Tendon/Ligament Repair and Regeneration. Adv. Mater. 2020, 32, e1904511. [Google Scholar] [CrossRef]
  145. Liu, R.; Zhang, S.; Chen, X. Injectable hydrogels for tendon and ligament tissue engineering. J. Tissue Eng. Regen. Med. 2020, 14, 1333–1348. [Google Scholar] [CrossRef]
  146. Dyment, N.A.; Barrett, J.G.; Awad, H.A.; Bautista, C.A.; Banes, A.J.; Butler, D.L. A brief history of tendon and ligament bioreactors: Impact and future prospects. J. Orthop. Res. 2020, 38, 2318–2330. [Google Scholar] [CrossRef]
  147. Rinoldi, C.; Kijeńska-Gawrońska, E.; Khademhosseini, A.; Tamayol, A.; Swieszkowski, W. Fibrous Systems as Potential Solutions for Tendon and Ligament Repair, Healing, and Regeneration. Adv. Health Mater. 2021, 10, e2001305. [Google Scholar] [CrossRef]
  148. McRobb, J.; Kamil, K.H.; Ahmed, I.; Dhaif, F.; Metcalfe, A. Influence of platelet-rich plasma (PRP) analogues on healing and clinical outcomes following anterior cruciate ligament (ACL) reconstructive surgery: A systematic review. Eur. J. Orthop. Surg. Traumatol. 2022, 1–29. [Google Scholar] [CrossRef]
  149. Heidari, B.S.; Ruan, R.; Vahabli, E.; Chen, P.; De-Juan-Pardo, E.M.; Zheng, M.; Doyle, B. Natural, synthetic and commercially-available biopolymers used to regenerate tendons and ligaments. Bioact. Mater. 2023, 19, 179–197. [Google Scholar] [CrossRef]
  150. Hensler, D.; Illingworth, K.D.; Musahl, V.; Working, Z.M.; Kobayashi, T.; Miyawaki, M.; Lorenz, S.; Witt, M.; Irrgang, J.J.; Huard, J.; et al. Does fibrin clot really enhance graft healing after double-bundle ACL reconstruction in a caprine model? Knee Surg. Sports Traumatol. Arthrosc. 2015, 23, 669–679. [Google Scholar] [CrossRef]
  151. Sun, P.; Chen, S.; Liu, L.; Gao, X. Enhancement of Anterior cruciate ligament injury repairing using connective tissue growth factor in a rabbit model. Pak. J. Pharm. Sci. 2018, 31, 2873–2878. [Google Scholar]
  152. Wiig, M.E.; Amiel, D.; Vandeberg, J.; Kitabayashi, L.; Harwood, F.L.; Arfors, K.E. The early effect of high molecular weight hyaluronan (hyaluronic acid) on anterior cruciate ligament healing: An experimental study in rabbits. J. Orthop. Res. 1990, 8, 425–434. [Google Scholar] [CrossRef]
  153. Cristino, S.; Grassi, F.; Toneguzzi, S.; Piacentini, A.; Grigolo, B.; Santi, S.; Riccio, M.; Tognana, E.; Facchini, A.; Lisignoli, G. Analysis of mesenchymal stem cells grown on a three-dimensional HYAFF 11®-based prototype ligament scaffold. J. Biomed. Mater. Res. Part A 2005, 73A, 275–283. [Google Scholar] [CrossRef]
  154. Berry, S.M.; Green, M.H.; Amiel, D. Hyaluronan: A potential carrier for growth factors for the healing of ligamentous tissues. Wound Repair Regen. 1997, 5, 33–38. [Google Scholar] [CrossRef]
  155. Wang, Y.; Shimmin, A.; Ghosh, P.; Marks, P.; Linklater, J.; Connell, D.; Hall, S.; Skerrett, D.; Itescu, S.; Cicuttini, F.M. Safety, tolerability, clinical, and joint structural outcomes of a single intra-articular injection of allogeneic mesenchymal precursor cells in patients following anterior cruciate ligament reconstruction: A controlled double-blind randomised trial. Arthritis Res. Ther. 2017, 19, 180. [Google Scholar] [CrossRef]
  156. Masuko, T.; Iwasaki, N.; Yamane, S.; Funakoshi, T.; Majima, T.; Minami, A.; Ohsuga, N.; Ohta, T.; Nishimura, S.-I. Chitosan–RGDSGGC conjugate as a scaffold material for musculoskeletal tissue engineering. Biomaterials 2005, 26, 5339–5347. [Google Scholar] [CrossRef]
  157. Dunn, M.; Tria, A.J.; Kato, Y.P.; Bechler, J.R.; Ochner, R.S.; Zawadsky, J.P.; Silver, F.H. Anterior cruciate ligament reconstruction using a composite collagenous prosthesis. Am. J. Sport. Med. 1992, 20, 507–515. [Google Scholar] [CrossRef]
  158. Chvapil, M.; Speer, D.P.; Holubec, H.; Chvapil, T.A.; King, D.H. Collagen fibers as a temporary scaffold for replacement of ACL in goats. J. Biomed. Mater. Res. 1993, 27, 313–325. [Google Scholar] [CrossRef]
  159. Dunn, M.G.; Liesch, J.B.; Tiku, M.L.; Zawadsky, J.P. Development of fibroblast-seeded ligament analogs for ACL reconstruction. J. Biomed. Mater. Res. 1995, 29, 1363–1371. [Google Scholar] [CrossRef]
  160. Bellincampi, L.D.; Closkey, R.F.; Prasad, R.; Zawadsky, J.P.; Dunn, M.G. Viability of fibroblast-seeded ligament analogs after autogenous implantation. J. Orthop. Res. 1998, 16, 414–420. [Google Scholar] [CrossRef]
  161. Gentleman, E.; Lay, A.N.; Dickerson, D.A.; Nauman, E.A.; Livesay, G.A.; Dee, K.C. Mechanical characterization of collagen fibers and scaffolds for tissue engineering. Biomaterials 2003, 24, 3805–3813. [Google Scholar] [CrossRef]
  162. Caruso, A.B.; Dunn, M.G. Changes in mechanical properties and cellularity during long-term culture of collagen fiber ACL reconstruction scaffolds. J. Biomed. Mater. Res. Part A 2005, 73A, 388–397. [Google Scholar] [CrossRef] [PubMed]
  163. Nöth, U.; Schupp, K.; Heymer, A.; Kall, S.; Jakob, F.; Schütze, N.; Baumann, B.; Barthel, T.; Eulert, J.; Hendrich, C. Anterior cruciate ligament constructs fabricated from human mesenchymal stem cells in a collagen type I hydrogel. Cytotherapy 2005, 7, 447–455. [Google Scholar] [CrossRef] [PubMed]
  164. Murray, M.M.; Spindler, K.P.; Abreu, E.; Muller, J.A.; Nedder, A.; Kelly, M.; Frino, J.; Zurakowski, D.; Valenza, M.; Snyder, B.D.; et al. Collagen-platelet rich plasma hydrogel enhances primary repair of the porcine anterior cruciate ligament. J. Orthop. Res. 2006, 25, 81–91. [Google Scholar] [CrossRef] [PubMed]
  165. Little, D.; Guilak, F.; Ruch, D.S. Ligament-Derived Matrix Stimulates a Ligamentous Phenotype in Human Adipose-Derived Stem Cells. Tissue Eng. Part A 2010, 16, 2307–2319. [Google Scholar] [CrossRef]
  166. Robayo, L.M.; Moulin, V.; Tremblay, P.; Cloutier, R.; Lamontagne, J.; Larkin, A.-M.; Chabaud, S.; Simon, F.; Islam, N.; Goulet, F. New ligament healing model based on tissue-engineered collagen scaffolds. Wound Repair Regen. 2011, 19, 38–48. [Google Scholar] [CrossRef]
  167. Figueroa, D.; Espinosa, M.; Calvo, R.; Scheu, M.; Vaisman, A.; Gallegos, M.; Conget, P. Anterior cruciate ligament regeneration using mesenchymal stem cells and collagen type I scaffold in a rabbit model. Knee Surg. Sport. Traumatol. Arthrosc. 2014, 22, 1196–1202. [Google Scholar] [CrossRef]
  168. Full, S.M.; Delman, C.; Gluck, J.; Abdmaulen, R.; Shemin, R.J.; Heydarkhan-Hagvall, S. Effect of fiber orientation of collagen-based electrospun meshes on human fibroblasts for ligament tissue engineering applications. J. Biomed. Mater. Res. Part B Appl. Biomater. 2015, 103, 39–46. [Google Scholar] [CrossRef]
  169. Altman, G.H.; Horan, R.L.; Lu, H.H.; Moreau, J.; Martin, I.; Richmond, J.C.; Kaplan, D.L. Silk matrix for tissue engineered anterior cruciate ligaments. Biomaterials 2002, 23, 4131–4141. [Google Scholar] [CrossRef]
  170. Altman, G.H.; Lu, H.H.; Horan, R.L.; Calabro, T.; Ryder, D.; Kaplan, D.L.; Stark, P.; Martin, I.; Richmond, J.C.; Vunjak-Novakovic, G. Advanced Bioreactor with Controlled Application of Multi-Dimensional Strain for Tissue Engineering. J. Biomech. Eng. 2002, 124, 742–749. [Google Scholar] [CrossRef]
  171. Chen, J.; Altman, G.H.; Karageorgiou, V.; Horan, R.; Collette, A.; Volloch, V.; Colabro, T.; Kaplan, D.L. Human bone marrow stromal cell and ligament fibroblast responses on RGD-modified silk fibers. J. Biomed. Mater. Res. 2003, 67A, 559–570. [Google Scholar] [CrossRef]
  172. Moreau, J.E.; Chen, J.; Horan, R.L.; Kaplan, D.L.; Altman, G.H. Sequential Growth Factor Application in Bone Marrow Stromal Cell Ligament Engineering. Tissue Eng. 2005, 11, 1887–1897. [Google Scholar] [CrossRef]
  173. Liu, H.; Ge, Z.; Wang, Y.; Toh, S.L.; Sutthikhum, V.; Goh, J.C.H. Modification of sericin-free silk fibers for ligament tissue engineering application. J. Biomed. Mater. Res. Part B Appl. Biomater. 2007, 82B, 129–138. [Google Scholar] [CrossRef]
  174. Chen, J.; Horan, R.L.; Bramono, D.; Moreau, J.E.; Wang, Y.; Geuss, L.R.; Collette, A.L.; Volloch, V.; Altman, G.H. Monitoring Mesenchymal Stromal Cell Developmental Stage to Apply On-Time Mechanical Stimulation for Ligament Tissue Engineering. Tissue Eng. 2006, 12, 3085–3095. [Google Scholar] [CrossRef]
  175. Liu, H.; Fan, H.; Wang, Y.; Toh, S.L.; Goh, J.C. The interaction between a combined knitted silk scaffold and microporous silk sponge with human mesenchymal stem cells for ligament tissue engineering. Biomaterials 2008, 29, 662–674. [Google Scholar] [CrossRef]
  176. Liu, H.; Fan, H.; Toh, S.L.; Goh, J.C. A comparison of rabbit mesenchymal stem cells and anterior cruciate ligament fibroblasts responses on combined silk scaffolds. Biomaterials 2008, 29, 1443–1453. [Google Scholar] [CrossRef]
  177. Fan, H.; Liu, H.; Wong, E.J.; Toh, S.L.; Goh, J.C. In vivo study of anterior cruciate ligament regeneration using mesenchymal stem cells and silk scaffold. Biomaterials 2008, 29, 3324–3337. [Google Scholar] [CrossRef]
  178. Seo, Y.-K.; Yoon, H.-H.; Song, K.-Y.; Kwon, S.-Y.; Lee, H.-S.; Park, Y.-S.; Park, J.-K. Increase in cell migration and angiogenesis in a composite silk scaffold for tissue-engineered ligaments. J. Orthop. Res. 2009, 27, 495–503. [Google Scholar] [CrossRef]
  179. Horan, R.; Toponarski, I.; Boepple, H.; Weitzel, P.; Richmond, J.; Altman, G. Design and Characterization of a Scaffold for Anterior Cruciate Ligament Engineering. J. Knee Surg. 2009, 22, 82–92. [Google Scholar] [CrossRef]
  180. Fan, H.; Liu, H.; Toh, S.L.; Goh, J.C. Anterior cruciate ligament regeneration using mesenchymal stem cells and silk scaffold in large animal model. Biomaterials 2009, 30, 4967–4977. [Google Scholar] [CrossRef]
  181. Teh, T.K.; Toh, S.L.; Goh, J.C. Aligned hybrid silk scaffold for enhanced differentiation of mesenchymal stem cells into ligament fibroblasts. Tissue Eng. Part C Methods 2011, 17, 687–703. [Google Scholar] [CrossRef] [PubMed]
  182. Li, X.; Snedeker, J. Wired silk architectures provide a biomimetic ACL tissue engineering scaffold. J. Mech. Behav. Biomed. Mater. 2013, 22, 30–40. [Google Scholar] [CrossRef] [PubMed]
  183. Teuschl, A.; Heimel, P.; Nurnberger, S.; van Griensven, M.; Redl, H.; Nau, T. A novel silk fiber-based scaffold for regeneration of the anterior cruciate ligament: Histological results from a study in sheep. Am. J. Sports Med. 2016, 44, 1547–1557. [Google Scholar] [CrossRef] [PubMed]
  184. Lin, V.S.; Lee, M.C.; O’Neal, S.; McKean, J.; Sung, K.-L.P. Ligament Tissue Engineering Using Synthetic Biodegradable Fiber Scaffolds. Tissue Eng. 1999, 5, 443–451. [Google Scholar] [CrossRef] [PubMed]
  185. Cabaud, H.E.; Feagin, J.A.; Rodkey, W.G. Acute anterior cruciate ligament injury and repair reinforced with a biodegradable intraarticular ligament. Am. J. Sport. Med. 1982, 10, 259–265. [Google Scholar] [CrossRef]
  186. Lu, H.H.; Cooper, J.A.; Manuel, S.; Freeman, J.W.; Attawia, M.A.; Ko, F.K.; Laurencin, C.T. Anterior cruciate ligament regeneration using braided biodegradable scaffolds: In vitro optimization studies. Biomaterials 2005, 26, 4805–4816. [Google Scholar] [CrossRef]
  187. Dürselen, L.; Dauner, M.; Hierlemann, H.; Planck, H.; Claes, L.E.; Ignatius, A. Resorbable polymer fibers for ligament augmentation. J. Biomed. Mater. Res. 2001, 58, 666–672. [Google Scholar] [CrossRef]
  188. Cooper, J.A.; Lu, H.H.; Ko, F.K.; Freeman, J.W.; Laurencin, C.T. Fiber-based tissue-engineered scaffold for ligament replacement: Design considerations and in vitro evaluation. Biomaterials 2005, 26, 1523–1532. [Google Scholar] [CrossRef]
  189. Cooper, J.A.; Bailey, L.O.; Carter, J.N.; Castiglioni, C.E.; Kofron, M.D.; Ko, F.K.; Laurencin, C.T. Evaluation of the anterior cruciate ligament, medial collateral ligament, achilles tendon and patellar tendon as cell sources for tissue-engineered ligament. Biomaterials 2006, 27, 2747–2754. [Google Scholar] [CrossRef]
  190. Heckmann, L.; Schlenker, H.-J.; Fiedler, J.; Brenner, R.; Dauner, M.; Bergenthal, G.; Mattes, T.; Claes, L.; Ignatius, A. Human mesenchymal progenitor cell responses to a novel textured poly(L-lactide) scaffold for ligament tissue engineering. J. Biomed. Mater. Res. Part B Appl. Biomater. 2007, 81B, 82–90. [Google Scholar] [CrossRef]
  191. Freeman, J.W.; Woods, M.D.; Laurencin, C.T. Tissue engineering of the anterior cruciate ligament using a braid–twist scaffold design. J. Biomech. 2007, 40, 2029–2036. [Google Scholar] [CrossRef] [Green Version]
  192. Freeman, J.W.; Woods, M.D.; Cromer, D.A.; Wright, L.D.; Laurencin, C.T. Tissue Engineering of the Anterior Cruciate Ligament: The Viscoelastic Behavior and Cell Viability of a Novel Braid–Twist Scaffold. J. Biomater. Sci. Polym. Ed. 2009, 20, 1709–1728. [Google Scholar] [CrossRef]
  193. Freeman, J.W.; Woods, M.D.; Cromer, D.A.; Ekwueme, E.C.; Andric, T.; Atiemo, E.A.; Bijoux, C.H.; Laurencin, C.T. Evaluation of a hydrogel–fiber composite for ACL tissue engineering. J. Biomech. 2011, 44, 694–699. [Google Scholar] [CrossRef]
  194. Kreja, L.; Liedert, A.; Schlenker, H.; Brenner, R.E.; Fiedler, J.; Friemert, B.; Dürselen, L.; Ignatius, A. Effects of mechanical strain on human mesenchymal stem cells and ligament fibroblasts in a textured poly(l-lactide) scaffold for ligament tissue engineering. J. Mater. Sci. Mater. Med. 2012, 23, 2575–2582. [Google Scholar] [CrossRef]
  195. Araque-Monrós, M.C.; Gamboa-Martínez, T.C.; Gil Santos, L.; Bernabé, S.G.; Pradas, M.M.; Estellés, J.M. New concept for a regenerative and resorbable prosthesis for tendon and ligament: Physicochemical and biological characterization of PLA-braided biomaterial. J. Biomed. Mater. Res. Part A 2013, 101, 3228–3237. [Google Scholar] [CrossRef]
  196. Van Eijk, F.; Saris, D.; Riesle, J.; Willems, W.; Van Blitterswijk, C.; Verbout, A.; Dhert, W.; Van Blitterswijk, C. Tissue Engineering of Ligaments: A Comparison of Bone Marrow Stromal Cells, Anterior Cruciate Ligament, and Skin Fibroblasts as Cell Source. Tissue Eng. 2004, 10, 893–903. [Google Scholar] [CrossRef]
  197. Sahoo, S.; Ouyang, H.; Goh, J.C.-H.; Tay, T.; Toh, S. Characterization of a Novel Polymeric Scaffold for Potential Application in Tendon/Ligament Tissue Engineering. Tissue Eng. 2006, 12, 91–99. [Google Scholar] [CrossRef] [Green Version]
  198. Jenner, J.; Van Eijk, F.; Saris, D.; Willems, W.; Dhert, W.; Creemers, L. Effect of Transforming Growth Factor-Beta and Growth Differentiation Factor-5 on Proliferation and Matrix Production by Human Bone Marrow Stromal Cells Cultured on Braided Poly Lactic-Co-Glycolic Acid Scaffolds for Ligament Tissue Engineering. Tissue Eng. 2007, 13, 1573–1582. [Google Scholar] [CrossRef]
  199. Petrigliano, F.A.; English, C.S.; Barba, D.; Esmende, S.; Wu, B.M.; McAllister, D.R. The Effects of Local bFGF Release and Uniaxial Strain on Cellular Adaptation and Gene Expression in a 3D Environment: Implications for Ligament Tissue Engineering. Tissue Eng. 2007, 13, 2721–2731. [Google Scholar] [CrossRef]
  200. Shao, H.J.; Chen, C.S.; Lee, Y.T.; Wang, J.H.; Young, T.H. The phenotypic responses of human anterior cruciate ligament cells cultured on poly(epsilon-caprolactone) and chitosan. J. Biomed. Mater. Res. A 2010, 93, 1297–1305. [Google Scholar]
  201. Peach, M.S.; Kumbar, S.G.; James, R.; Toti, U.S.; Balasubramaniam, D.; Deng, M.; Ulery, B.; Mazzocca, A.D.; McCarthy, M.B.; Morozowich, N.L.; et al. Design and optimization of polyphosphazene functionalized fiber matrices for soft tissue regeneration. J. Biomed. Nanotechnol. 2012, 8, 107–124. [Google Scholar] [CrossRef] [PubMed]
  202. Huot, S.; Rohman, G.; Riffault, M.; Pinzano, A.; Grossin, L.; Migonney, V. Increasing the bioactivity of elastomeric poly(epsilon-caprolactone) scaffolds for use in tissue engineering. Biomed Mater. Eng. 2013, 23, 281–288. [Google Scholar] [PubMed]
  203. Leong, N.L.; Kabir, N.; Arshi, A.; Nazemi, A.; Wu, B.; Petrigliano, F.A.; McAllister, D.R. Evaluation of Polycaprolactone Scaffold with Basic Fibroblast Growth Factor and Fibroblasts in an Athymic Rat Model for Anterior Cruciate Ligament Reconstruction. Tissue Eng. Part A 2015, 21, 1859–1868. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  204. Leroux, A.; Egles, C.; Migonney, V. Impact of chemical and physical treatments on the mechanical properties of poly(epsilon-caprolactone) fibers bundles for the anterior cruciate ligament reconstruction. PLoS ONE 2018, 13, e0205722. [Google Scholar] [CrossRef] [PubMed]
  205. Leroux, A.; Venkatesan, J.K.; Castner, D.G.; Cucchiarini, M.; Migonney, V. Analysis of early cellular responses of anterior cruciate ligament fibroblasts seeded on different molecular weight polycaprolactone films functionalized by a bioactive poly(sodium styrene sulfonate) polymer. Biointerphases 2019, 14, 041004. [Google Scholar] [CrossRef] [PubMed]
  206. Leroux, A.; Nguyen, T.N.; Rangel, A.; Cacciapuoti, I.; Duprez, D.; Castner, D.G.; Migonney, V. Long-term hydrolytic degradation study of polycaprolactone films and fibers grafted with poly(sodium styrene sulfonate): Mechanism study and cell response. Biointerphases 2020, 15, 061006. [Google Scholar] [CrossRef]
  207. Doroski, D.M.; Levenston, M.; Temenoff, J.S. Cyclic Tensile Culture Promotes Fibroblastic Differentiation of Marrow Stromal Cells Encapsulated in Poly(Ethylene Glycol)-Based Hydrogels. Tissue Eng. Part A 2010, 16, 3457–3466. [Google Scholar] [CrossRef] [Green Version]
  208. Ciobanu, M.; Siove, A.; Gueguen, V.; Gamble, L.J.; Castner, A.D.G.; Migonney, V. Radical Graft Polymerization of Styrene Sulfonate on Poly(ethylene terephthalate) Films for ACL Applications: “Grafting From” and Chemical Characterization. Biomacromolecules 2006, 7, 755–760. [Google Scholar] [CrossRef]
  209. Pavon-Djavid, G.; Gamble, L.J.; Ciobanu, M.; Gueguen, V.; Castner, A.D.G.; Migonney, V. Bioactive Poly(ethylene terephthalate) Fibers and Fabrics: Grafting, Chemical Characterization, and Biological Assessment. Biomacromolecules 2007, 8, 3317–3325. [Google Scholar] [CrossRef]
  210. Zhou, J.; Ciobanu, M.; Pavon-Djavid, G.; Gueguen, V.; Migonney, V. Morphology and adhesion of human fibroblast cells cultured on bioactive polymer grafted ligament prosthesis. Annu. Int. Conf. IEEE Eng. Med. Biol. Soc. 2007, 2007, 5115–5118. [Google Scholar]
  211. Vaquette, C.; Viateau, V.; Guérard, S.; Anagnostou, F.; Manassero, M.; Castner, D.G.; Migonney, V. The effect of polystyrene sodium sulfonate grafting on polyethylene terephthalate artificial ligaments on in vitro mineralisation and in vivo bone tissue integration. Biomaterials 2013, 34, 7048–7063. [Google Scholar] [CrossRef] [Green Version]
  212. Nguyen, T.N.; Rangel, A.; Grainger, D.W.; Migonney, V. Influence of spin finish on degradation, functionalization and long-term storage of polyethylene terephthalate fabrics dedicated to ligament prostheses. Sci. Rep. 2021, 11, 4258. [Google Scholar] [CrossRef]
  213. Murray, M.M.; Martin, S.D.; Spector, M. Migration of cells from human anterior cruciate ligament explants into collagen-glycosaminoglycan scaffolds. J. Orthop. Res. 2000, 18, 557–564. [Google Scholar] [CrossRef]
  214. Murray, M.M.; Spector, M. The migration of cells from the ruptured human anterior cruciate ligament into collagen-glycosaminoglycan regeneration templates in vitro. Biomaterials 2001, 22, 2393–2402. [Google Scholar] [CrossRef]
  215. Panas-Perez, E.; Gatt, C.J.; Dunn, M.G. Development of a silk and collagen fiber scaffold for anterior cruciate ligament reconstruction. J. Mater. Sci. Mater. Electron. 2013, 24, 257–265. [Google Scholar] [CrossRef]
  216. Shen, W.; Chen, X.; Hu, Y.; Yin, Z.; Zhu, T.; Hu, J.; Chen, J.; Zheng, Z.; Zhang, W.; Ran, J.; et al. Long-term effects of knitted silk–collagen sponge scaffold on anterior cruciate ligament reconstruction and osteoarthritis prevention. Biomaterials 2014, 35, 8154–8163. [Google Scholar] [CrossRef]
  217. Bi, F.; Shi, Z.; Liu, A.; Guo, P.; Yan, S. Anterior Cruciate Ligament Reconstruction in a Rabbit Model Using Silk-Collagen Scaffold and Comparison with Autograft. PLoS ONE 2015, 10, e0125900. [Google Scholar] [CrossRef]
  218. Tovar, N.; Murthy, N.S.; Kohn, J.; Gatt, C.; Dunn, M. ACL reconstruction using a novel hybrid scaffold composed of polyarylate fibers and collagen fibers. J. Biomed. Mater. Res. Part A 2012, 100A, 2913–2920. [Google Scholar] [CrossRef]
  219. Sahoo, S.; Toh, S.L.; Goh, J.C. A bFGF-releasing silk/PLGA-based biohybrid scaffold for ligament/tendon tissue engineering using mesenchymal progenitor cells. Biomaterials 2010, 31, 2990–2998. [Google Scholar] [CrossRef]
  220. Majima, T.; Irie, T.; Sawaguchi, N.; Funakoshi, T.; Iwasaki, N.; Harada, K.; Minami, A.; Nishimura, S.-I. Chitosan-based hyaluronan hybrid polymer fibre scaffold for ligament and tendon tissue engineering. Proc. Inst. Mech. Eng. Part H J. Eng. Med. 2007, 221, 537–546. [Google Scholar] [CrossRef]
  221. Sarukawa, J.; Takahashi, M.; Abe, M.; Suzuki, D.; Tokura, S.; Furuike, T.; Tamura, H. Effects of Chitosan-Coated Fibers as a Scaffold for Three-Dimensional Cultures of Rabbit Fibroblasts for Ligament Tissue Engineering. J. Biomater. Sci. Polym. Ed. 2011, 22, 717–732. [Google Scholar] [CrossRef] [PubMed]
  222. Shao, H.-J.; Lee, Y.-T.; Chen, C.-S.; Wang, J.-H.; Young, T.-H. Modulation of gene expression and collagen production of anterior cruciate ligament cells through cell shape changes on polycaprolactone/chitosan blends. Biomaterials 2010, 31, 4695–4705. [Google Scholar] [CrossRef] [PubMed]
  223. Vaquette, C.; Kahn, C.; Frochot, C.; Nouvel, C.; Six, J.-L.; De Isla, N.; Luo, L.-H.; Cooper-White, J.; Rahouadj, R.; Wang, X. Aligned poly(L-lactic-co-e-caprolactone) electrospun microfibers and knitted structure: A novel composite scaffold for ligament tissue engineering. J. Biomed. Mater. Res. Part A 2010, 94A, 1270–1282. [Google Scholar] [CrossRef] [PubMed]
  224. Ge, Z.; Goh, J.C.H.; Lee, E.H. The Effects of Bone Marrow-Derived Mesenchymal Stem Cells and Fascia Wrap Application to Anterior Cruciate Ligament Tissue Engineering. Cell Transplant. 2005, 14, 763–773. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  225. Murray, M.M.; Spindler, K.P.; Devin, C.; Snyder, B.S.; Muller, J.; Takahashi, M.; Ballard, P.; Nanney, L.B.; Zurakowski, D. Use of a collagen-platelet rich plasma scaffold to stimulate healing of a central defect in the canine ACL. J. Orthop. Res. 2006, 24, 820–830. [Google Scholar] [CrossRef]
  226. Murray, M.M.; Spindler, K.P.; Ballard, P.; Welch, T.P.; Zurakowski, D.; Nanney, L.B. Enhanced histologic repair in a central wound in the anterior cruciate ligament with a collagen–platelet-rich plasma scaffold. J. Orthop. Res. 2007, 25, 1007–1017. [Google Scholar] [CrossRef]
  227. Joshi, S.M.; Mastrangelo, A.N.; Magarian, E.M.; Fleming, B.C.; Murray, M.M. Collagen-Platelet Composite Enhances Biomechanical and Histologic Healing of the Porcine Anterior Cruciate Ligament. Am. J. Sport. Med. 2009, 37, 2401–2410. [Google Scholar] [CrossRef]
  228. Vavken, P.; Fleming, B.C.; Mastrangelo, A.N.; Machan, J.; Murray, M.M. Biomechanical Outcomes After Bioenhanced Anterior Cruciate Ligament Repair and Anterior Cruciate Ligament Reconstruction Are Equal in a Porcine Model. Arthrosc. J. Arthrosc. Relat. Surg. 2012, 28, 672–680. [Google Scholar] [CrossRef] [Green Version]
  229. Cheng, M.; Wang, H.; Yoshida, R.; Murray, M.M. Platelets and Plasma Proteins Are Both Required to Stimulate Collagen Gene Expression by Anterior Cruciate Ligament Cells in Three-Dimensional Culture. Tissue Eng. Part A 2010, 16, 1479–1489. [Google Scholar] [CrossRef] [Green Version]
  230. Xu, J.; Ye, Z.; Han, K.; Zheng, T.; Zhang, T.; Dong, S.; Jiang, J.; Yan, X.; Cai, J.; Zhao, J. Infrapatellar Fat Pad Mesenchymal Stromal Cell–Derived Exosomes Accelerate Tendon-Bone Healing and Intra-articular Graft Remodeling After Anterior Cruciate Ligament Reconstruction. Am. J. Sport. Med. 2022, 50, 662–673. [Google Scholar] [CrossRef]
  231. Li, Z.; Li, Q.; Tong, K.; Zhu, J.; Wang, H.; Chen, B.; Chen, L. BMSC-derived exosomes promote tendon-bone healing after anterior cruciate ligament reconstruction by regulating M1/M2 macrophage polarization in rats. Stem. Cell Res. Ther. 2022, 13, 295. [Google Scholar] [CrossRef]
  232. Fallouh, L.; Nakagawa, K.; Sasho, T.; Arai, M.; Kitahara, S.; Wada, Y.; Moriya, H.; Takahashi, K. Effects of Autologous Platelet-Rich Plasma on Cell Viability and Collagen Synthesis in Injured Human Anterior Cruciate Ligament. J. Bone Jt. Surg. 2010, 92, 2909–2916. [Google Scholar] [CrossRef] [Green Version]
  233. Vavken, P.; Sadoghi, P.; Murray, M.M. 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. Arthrosc. J. Arthrosc. Relat. Surg. 2011, 27, 1573–1583. [Google Scholar] [CrossRef] [Green Version]
  234. Xie, X.; Zhao, S.; Wu, H.; Xie, G.; Huangfu, X.; He, Y.; Zhao, J. Platelet-rich plasma enhances autograft revascularization and reinnervation in a dog model of anterior cruciate ligament reconstruction. J. Surg. Res. 2013, 183, 214–222. [Google Scholar] [CrossRef]
  235. Scull, G.; Fisher, M.B.; Brown, A.C. Fibrin-based biomaterial systems to enhance anterior cruciate ligament healing. Med. Devices Sensors 2021, 4, e10147. [Google Scholar] [CrossRef]
  236. Evans, C.H. Cytokines and the Role They Play in the Healing of Ligaments and Tendons. Sport. Med. 1999, 28, 71–76. [Google Scholar] [CrossRef]
  237. Woo, S.L.-Y.; Jia, F.; Zou, L.; Gabriel, M.T. Functional tissue engineering for ligament healing: Potential of antisense gene therapy. Ann. Biomed. Eng. 2004, 32, 342–351. [Google Scholar] [CrossRef]
  238. Gantenbein, B.; Tang, S.; Guerrero, J.; Higuita-Castro, N.; Salazar-Puerta, A.I.; Croft, A.S.; Gazdhar, A.; Purmessur, D. Non-viral Gene Delivery Methods for Bone and Joints. Front. Bioeng. Biotechnol. 2020, 8, 598466. [Google Scholar] [CrossRef]
  239. Zu, H.; Gao, D. Non-viral Vectors in Gene Therapy: Recent Development, Challenges, and Prospects. AAPS J. 2021, 23, 78. [Google Scholar] [CrossRef]
  240. Goins, W.F.; Hall, B.; Cohen, J.B.; Glorioso, J.C. Retargeting of herpes simplex virus (HSV) vectors. Curr. Opin. Virol. 2016, 21, 93–101. [Google Scholar] [CrossRef] [Green Version]
  241. Greber, U.F.; Gomez-Gonzalez, A. Adenovirus—A blueprint for gene delivery. Curr. Opin. Virol. 2021, 48, 49–56. [Google Scholar] [CrossRef] [PubMed]
  242. Watanabe, M.; Nishikawaji, Y.; Kawakami, H.; Kosai, K.-I. Adenovirus Biology, Recombinant Adenovirus, and Adenovirus Usage in Gene Therapy. Viruses 2021, 13, 2502. [Google Scholar] [CrossRef] [PubMed]
  243. Elsner, C.; Bohne, J. The retroviral vector family: Something for everyone. Virus Genes 2017, 53, 714–722. [Google Scholar] [CrossRef] [PubMed]
  244. Milone, M.C.; O’Doherty, U. Clinical use of lentiviral vectors. Leukemia 2018, 32, 1529–1541. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  245. Li, C.; Samulski, R.J. Engineering adeno-associated virus vectors for gene therapy. Nat. Rev. Genet. 2020, 21, 255–272. [Google Scholar] [CrossRef] [PubMed]
  246. Maurer, A.C.; Weitzman, M.D. Adeno-Associated Virus Genome Interactions Important for Vector Production and Transduction. Hum. Gene Ther. 2020, 31, 499–511. [Google Scholar] [CrossRef] [PubMed]
  247. Cottard, V.; Valvason, C.; Falgarone, G.; Lutomski, D.; Boissier, M.-C.; Bessis, N. Immune Response Against Gene Therapy Vectors: Influence of Synovial Fluid on Adeno-Associated Virus Mediated Gene Transfer to Chondrocytes. J. Clin. Immunol. 2004, 24, 162–169. [Google Scholar] [CrossRef]
  248. Mingozzi, F.; Chen, Y.; Edmonson, S.; Zhou, S.; Thurlings, R.M.; Tak, P.P.; High, K.; Vervoordeldonk, M.J. Prevalence and pharmacological modulation of humoral immunity to AAV vectors in gene transfer to synovial tissue. Gene Ther. 2013, 20, 417–424. [Google Scholar] [CrossRef]
  249. Verdera, H.C.; Kuranda, K.; Mingozzi, F. AAV Vector Immunogenicity in Humans: A Long Journey to Successful Gene Transfer. Mol. Ther. 2020, 28, 723–746. [Google Scholar] [CrossRef]
  250. Murphy, P.G.; Loitz, B.J.; Frank, C.B.; Hart, D.A. Influence of exogenous growth factors on the synthesis and secretion of collagen types I and III by explants of normal and healing rabbit ligaments. Biochem. Cell Biol. 1994, 72, 403–409. [Google Scholar] [CrossRef]
  251. Schmidt, C.C.; Georgescu, H.I.; Kwoh, C.K.; Blomstrom, G.L.; Engle, C.P.; Larkin, L.A.; Evans, C.H.; Woo, S.L.-Y. Effect of growth factors on the proliferation of fibroblasts from the medial collateral and anterior cruciate ligaments. J. Orthop. Res. 1995, 13, 184–190. [Google Scholar] [CrossRef]
  252. Desrosiers, E.A.; Yahia, L.; Rivard, C.-H. Proliferative and matrix synthesis response of canine anterior cruciate ligament fibroblasts submitted to combined growth factors. J. Orthop. Res. 1996, 14, 200–208. [Google Scholar] [CrossRef]
  253. Spindler, K.P.; Imro, A.K.; Mayes, C.E.; Davidson, J.M. Patellar tendon and anterior cruciate ligament have different mitogenic responses to platelet-derived growth factor and transforming growth factor beta. J. Orthop. Res. 1996, 14, 542–546. [Google Scholar] [CrossRef]
  254. Marui, T.; Niyibizi, C.; Georgescu, H.I.; Cao, M.; Kavalkovich, K.W.; Levine, R.E.; Woo, S.L.-Y. Effect of growth factors on matrix synthesis by ligament fibroblasts. J. Orthop. Res. 1997, 15, 18–23. [Google Scholar] [CrossRef]
  255. Yoshida, M.; Fujii, K. Differences in cellular properties and responses to growth factors between human ACL and MCL cells. J. Orthop. Sci. 1999, 4, 293–298. [Google Scholar] [CrossRef]
  256. Murray, M.M.; Rice, K.; Wright, R.J.; Spector, M. The effect of selected growth factors on human anterior cruciate ligament cell interactions with a three-dimensional collagen-GAG scaffold. J. Orthop. Res. 2003, 21, 238–244. [Google Scholar] [CrossRef]
  257. Okuizumi, T.; Tohyama, H.; Kondo, E.; Yasuda, K. The effect of cell-based therapy with autologous synovial fibroblasts activated by exogenous TGF-beta1 on the in situ frozen-thawed anterior cruciate ligament. J. Orthop. Sci. 2004, 9, 488–494. [Google Scholar] [CrossRef]
  258. Kondo, E.; Yasuda, K.; Yamanaka, M.; Minami, A.; Tohyama, H. Effects of Administration of Exogenous Growth Factors on Biomechanical Properties of the Elongation-type Anterior Cruciate Ligament Injury with Partial Laceration. Am. J. Sport. Med. 2005, 33, 188–196. [Google Scholar] [CrossRef]
  259. Wolfman, N.M.; Hattersley, G.; Cox, K.; Celeste, A.J.; Nelson, R.; Yamaji, N.; Dube, J.L.; DiBlasio-Smith, E.; Nove, J.; Song, J.J.; et al. Ectopic induction of tendon and ligament in rats by growth and differentiation factors 5, 6, and 7, members of the TGF-beta gene family. J. Clin. Investig. 1997, 100, 321–330. [Google Scholar] [CrossRef] [Green Version]
  260. Hannafin, J.A.; Attia, E.T.; Warren, R.F.; Bhargava, M.M. Characterization of chemotactic migration and growth kinetics of canine knee ligament fibroblasts. J. Orthop. Res. 1999, 17, 398–404. [Google Scholar] [CrossRef]
  261. Tashiro, T.; Hiraoka, H.; Ikeda, Y.; Ohnuki, T.; Suzuki, R.; Ochi, T.; Nakamura, K.; Fukui, N. Effect of GDF-5 on ligament healing. J. Orthop. Res. 2006, 24, 71–79. [Google Scholar] [CrossRef] [PubMed]
  262. Date, H.; Furumatsu, T.; Sakoma, Y.; Yoshida, A.; Hayashi, Y.; Abe, N.; Ozaki, T. GDF-5/7 and bFGF activate integrin alpha2-mediated cellular migration in rabbit ligament fibroblasts. J. Orthop. Res. 2010, 28, 225–231. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  263. Amiel, D.; Nagineni, C.N.; Choi, S.H.; Lee, J. Intrinsic properties of ACL and MCL cells and their responses to growth factors. Med. Sci. Sport. Exerc. 1995, 27, 844–851. [Google Scholar] [CrossRef]
  264. Letson, A.K.; E Dahners, L. The effect of combinations of growth factors on ligament healing. Clin. Orthop. Relat. Res. 1994, 308, 207–212. [Google Scholar] [CrossRef]
  265. Scherping, S.C.; Schmidt, C.C.; Georgescu, H.I.; Kwoh, C.K.; Evans, C.H.; Woo, S.L.-Y. Effect of Growth Factors on the Proliferation of Ligament Fibroblasts from Skeletally Mature Rabbits. Connect. Tissue Res. 1997, 36, 1–8. [Google Scholar] [CrossRef] [PubMed]
  266. Kobayashi, D.; Kurosaka, M.; Yoshiya, S.; Mizuno, K. Effect of basic fibroblast growth factor on the healing of defects in the canine anterior cruciate ligament. Knee Surg. Sport. Traumatol. Arthrosc. 1997, 5, 189–194. [Google Scholar] [CrossRef]
  267. Lee, J.; Green, M.H.; Amiel, D. Synergistic effect of growth factors on cell outgrowth from explants of rabbit anterior cruciate and medial collateral ligaments. J. Orthop. Res. 1995, 13, 435–441. [Google Scholar] [CrossRef]
  268. Weiler, A.; Förster, C.; Hunt, P.; Falk, R.; Jung, T.; Unterhauser, F.N.; Bergmann, V.; Schmidmaier, G.; Haas, N.P. The Influence of Locally Applied Platelet-Derived Growth Factor-BB on Free Tendon Graft Remodeling after Anterior Cruciate Ligament Reconstruction. Am. J. Sport. Med. 2004, 32, 881–891. [Google Scholar] [CrossRef]
  269. Mckean, J.M.; Hsieh, A.H.; Sung, K.L.P. Epidermal growth factor differentially affects integrin-mediated adhesion and proliferation of ACL and MCL fibroblasts. Biorheology 2004, 41, 139–152. [Google Scholar]
  270. Woo, Y.K.; Kwon, S.Y.; Lee, H.S.; Park, Y.S. Proliferation of anterior cruciate ligament cells in vitro by photo-immobilized epidermal growth factor. J. Orthop. Res. 2007, 25, 73–80. [Google Scholar] [CrossRef]
  271. Ju, Y.-J.; Tohyama, H.; Kondo, E.; Yoshikawa, T.; Muneta, T.; Shinomiya, K.; Yasuda, K. Effects of Local Administration of Vascular Endothelial Growth Factor on Properties of the in Situ Frozen-Thawed Anterior Cruciate Ligament in Rabbits. Am. J. Sport. Med. 2006, 34, 84–91. [Google Scholar] [CrossRef]
  272. Yoshikawa, T.; Tohyama, H.; Katsura, T.; Kondo, E.; Kotani, Y.; Matsumoto, H.; Toyama, Y.; Yasuda, K. Effects of Local Administration of Vascular Endothelial Growth Factor on Mechanical Characteristics of the Semitendinosus Tendon Graft after Anterior Cruciate Ligament Reconstruction in Sheep. Am. J. Sport. Med. 2006, 34, 1918–1925. [Google Scholar] [CrossRef]
  273. Caceres, M.D.; Pfeifer, C.G.; Docheva, D. Understanding Tendons: Lessons from Transgenic Mouse Models. Stem Cells Dev. 2018, 27, 1161–1174. [Google Scholar] [CrossRef]
  274. Murchison, N.D.; Price, B.A.; Conner, D.A.; Keene, D.R.; Olson, E.N.; Tabin, C.J.; Schweitzer, R. Regulation of tendon differentiation by scleraxis distinguishes force-transmitting tendons from muscle-anchoring tendons. Development 2007, 134, 2697–2708. [Google Scholar] [CrossRef] [Green Version]
  275. Alberton, P.; Popov, C.; Prägert, M.; Kohler, J.; Shukunami, C.; Schieker, M.; Docheva, D. Conversion of Human Bone Marrow-Derived Mesenchymal Stem Cells into Tendon Progenitor Cells by Ectopic Expression of Scleraxis. Stem Cells Dev. 2012, 21, 846–858. [Google Scholar] [CrossRef] [Green Version]
  276. Chen, X.; Yin, Z.; Chen, J.-L.; Shen, W.-L.; Liu, H.-H.; Tang, Q.-M.; Fang, Z.; Lu, L.-R.; Ji, J.; Ouyang, H.-W. Force and scleraxis synergistically promote the commitment of human ES cells derived MSCs to tenocytes. Sci. Rep. 2012, 2, 977. [Google Scholar] [CrossRef] [Green Version]
  277. Dyment, N.A.; Liu, C.-F.; Kazemi, N.; Aschbacher-Smith, L.E.; Kenter, K.; Breidenbach, A.P.; Shearn, J.T.; Wylie, C.; Rowe, D.W.; Butler, D.L. The Paratenon Contributes to Scleraxis-Expressing Cells during Patellar Tendon Healing. PLoS ONE 2013, 8, e59944. [Google Scholar] [CrossRef] [Green Version]
  278. Nichols, A.E.; Werre, S.R.; Dahlgren, L.A. Transient Scleraxis Overexpression Combined with Cyclic Strain Enhances Ligament Cell Differentiation. Tissue Eng. Part A 2018, 24, 1444–1455. [Google Scholar] [CrossRef]
  279. Zhu, X.; Liu, Z.; Wu, S.; Li, Y.; Xiong, H.; Zou, G.; Jin, Y.; Yang, J.; You, Q.; Zhang, J.; et al. Enhanced tenogenic differentiation and tendon-like tissue formation by Scleraxis overexpression in human amniotic mesenchymal stem cells. Histochem. J. 2020, 51, 209–220. [Google Scholar] [CrossRef]
  280. Ito, Y.; Toriuchi, N.; Yoshitaka, T.; Ueno-Kudoh, H.; Sato, T.; Yokoyama, S.; Nishida, K.; Akimoto, T.; Takahashi, M.; Miyaki, S.; et al. The Mohawk homeobox gene is a critical regulator of tendon differentiation. Proc. Natl. Acad. Sci. USA 2010, 107, 10538–10542. [Google Scholar] [CrossRef] [Green Version]
  281. Nakahara, H.; Hasegawa, A.; Otabe, K.; Ayabe, F.; Matsukawa, T.; Onizuka, N.; Ito, Y.; Ozaki, T.; Lotz, M.K.; Asahara, H. Transcription Factor Mohawk and the Pathogenesis of Human Anterior Cruciate Ligament Degradation. Arthritis Care Res. 2013, 65, 2081–2089. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  282. Otabe, K.; Nakahara, H.; Hasegawa, A.; Matsukawa, T.; Ayabe, F.; Onizuka, N.; Inui, M.; Takada, S.; Ito, Y.; Sekiya, I.; et al. Transcription factor Mohawk controls tenogenic differentiation of bone marrow mesenchymal stem cells in vitro and in vivo. J. Orthop. Res. 2015, 33, 1–8. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  283. Kataoka, K.; Kurimoto, R.; Tsutsumi, H.; Chiba, T.; Kato, T.; Shishido, K.; Kato, M.; Ito, Y.; Cho, Y.; Hoshi, O.; et al. In vitro Neo-Genesis of Tendon/Ligament-Like Tissue by Combination of Mohawk and a Three-Dimensional Cyclic Mechanical Stretch Culture System. Front. Cell Dev. Biol. 2020, 8, 307. [Google Scholar] [CrossRef]
  284. Cameron, M.L.; Fu, F.H.; Paessler, H.H.; Schneider, M.; Evans, C.H. Synovial fluid cytokine concentrations as possible prognostic indicators in the ACL-deficient knee. Knee Surg. Sport. Traumatol. Arthrosc. 1994, 2, 38–44. [Google Scholar] [CrossRef] [PubMed]
  285. Lohmander, L.S.; Roos, H.; Dahlberg, L.; Hoerrner, L.A.; Lark, M.W. Temporal patterns of stromelysin-1, tissue inhibitor, and proteoglycan fragments in human knee joint fluid after injury to the cruciate ligament or meniscus. J. Orthop. Res. 1994, 12, 21–28. [Google Scholar] [CrossRef]
  286. Irie, K.; Uchiyama, E.; Iwaso, H. Intraarticular inflammatory cytokines in acute anterior cruciate ligament injured knee. Knee 2003, 10, 93–96. [Google Scholar] [CrossRef]
  287. Higuchi, H.; Shirakura, K.; Kimura, M.; Terauchi, M.; Shinozaki, T.; Watanabe, H.; Takagishi, K. Changes in biochemical parameters after anterior cruciate ligament injury. Int. Orthop. 2006, 30, 43–47. [Google Scholar] [CrossRef] [Green Version]
  288. Murakami, H.; Shinomiya, N.; Kikuchi, T.; Yoshihara, Y.; Nemoto, K. Upregulated expression of inducible nitric oxide synthase plays a key role in early apoptosis after anterior cruciate ligament injury. J. Orthop. Res. 2006, 24, 1521–1534. [Google Scholar] [CrossRef]
  289. Tang, Z.; Yang, L.; Xue, R.; Zhang, J.; Wang, Y.; Chen, P.C.; Sung, K.L. Differential expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in anterior cruciate ligament and medial collateral ligament fibroblasts after a mechanical injury: Involvement of the p65 subunit of NF-kappaB. Wound Repair Regen. 2009, 17, 709–716. [Google Scholar] [CrossRef]
  290. Xie, J.; Wang, C.; Yin, L.; Xu, C.; Zhang, Y.; Sung, K.-L.P. Interleukin-1 beta influences on lysyl oxidases and matrix metalloproteinases profile of injured anterior cruciate ligament and medial collateral ligament fibroblasts. Int. Orthop. 2013, 37, 495–505. [Google Scholar] [CrossRef] [Green Version]
  291. Bigoni, M.; Sacerdote, P.; Turati, M.; Franchi, S.; Gandolla, M.; Gaddi, D.; Moretti, S.; Munegato, D.; Augusti, C.A.; Bresciani, E.; et al. Acute and late changes in intraarticular cytokine levels following anterior cruciate ligament injury. J. Orthop. Res. 2013, 31, 315–321. [Google Scholar] [CrossRef]
  292. Xie, J.; Jiang, J.; Huang, W.; Zhang, Y.; Xu, C.; Wang, C.; Yin, L.; Chen, P.C.; Sung, K.P. TNF-α induced down-regulation of lysyl oxidase family in anterior cruciate ligament and medial collateral ligament fibroblasts. Knee 2014, 21, 47–53. [Google Scholar] [CrossRef]
  293. Struglics, A.; Larsson, S.; Kumahashi, N.; Frobell, R.; Lohmander, L.S. Changes in cytokines and aggrecan ARGS neoepitope in synovial fluid and serum and in C-terminal crosslinking telopeptide of type II collagen and N-terminal crosslinking telopeptide of type I collagen in urine over five years after anterior cruciate ligament rupture: An exploratory analysis in the knee anterior cruciate ligament, nonsurgical versus surgical treatment trial. Arthritis Rheumatol. 2015, 67, 1816–1825. [Google Scholar]
  294. Chamberlain, C.S.; Leiferman, E.M.; Frisch, K.E.; Kuehl, S.; Brickson, S.L.; Murphy, W.L.; Baer, G.S.; Vanderby, R. Interleukin-1 receptor antagonist modulates inflammation and scarring after ligament injury. Connect. Tissue Res. 2014, 55, 177–186. [Google Scholar] [CrossRef] [Green Version]
  295. Chamberlain, C.S.; Leiferman, E.M.; Frisch, K.E.; Brickson, S.L.; Murphy, W.L.; Baer, G.S.; Vanderby, R. Interleukin Expression after Injury and the Effects of Interleukin-1 Receptor Antagonist. PLoS ONE 2013, 8, e71631. [Google Scholar] [CrossRef]
  296. Lawrence, J.T.R.; Birmingham, J.; Toth, A.P. Emerging Ideas: Prevention of Posttraumatic Arthritis Through Interleukin-1 and Tumor Necrosis Factor-alpha Inhibition. Clin. Orthop. Relat. Res. 2011, 469, 3522–3526. [Google Scholar] [CrossRef] [Green Version]
  297. Kraus, V.B.; Birmingham, J.; Stabler, T.V.; Feng, S.; Taylor, D.C.; Moorman, C.T., 3rd; Garrett, W.E.; Toth, A.P. Effects of intraarticular IL1-Ra for acute anterior cruciate ligament knee injury: A randomized controlled pilot trial (NCT00332254). Osteoarthr. Cartil. 2012, 20, 271–278. [Google Scholar] [CrossRef] [Green Version]
  298. Ricchetti, E.T.; Reddy, S.C.; Ansorge, H.L.; Zgonis, M.H.; Van Kleunen, J.P.; Liechty, K.W.; Soslowsky, L.J.; Beredjiklian, P.K. Effect of Interleukin-10 Overexpression on the Properties of Healing Tendon in a Murine Patellar Tendon Model. J. Hand Surg. 2008, 33, 1843–1852. [Google Scholar] [CrossRef]
  299. Bigoni, M.; Zanchi, N.; Omeljaniuk, R.J.; Zatti, G.; Locatelli, V.; Torsello, A.; Turati, M. Role of interleukin-10 in the synovial fluid of the anterior cruciate ligament injured knee. Eur. Rev. Med. Pharmacol. Sci. 2019, 23, 932–940. [Google Scholar]
  300. Wang, C.; Sha, Y.; Wang, S.; Chi, Q.; Sung, K.P.; Xu, K.; Yang, L. Lysyl oxidase suppresses the inflammatory response in anterior cruciate ligament fibroblasts and promotes tissue regeneration by targeting myotrophin via the nuclear factor-kappa B pathway. J. Tissue Eng. Regen. Med. 2020, 14, 1063–1076. [Google Scholar] [CrossRef]
  301. Sun, M.; Connizzo, B.K.; Adams, S.M.; Freedman, B.R.; Wenstrup, R.J.; Soslowsky, L.J.; Birk, D.E. Targeted Deletion of Collagen V in Tendons and Ligaments Results in a Classic Ehlers-Danlos Syndrome Joint Phenotype. Am. J. Pathol. 2015, 185, 1436–1447. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  302. Evangelopoulos, D.S.; Kohl, S.; Schwienbacher, S.; Gantenbein, B.; Exadaktylos, A.; Ahmad, S.S. Collagen application reduces complication rates of mid-substance ACL tears treated with dynamic intraligamentary stabilization. Knee Surg. Sport. Traumatol. Arthrosc. 2017, 25, 2414–2419. [Google Scholar] [CrossRef] [PubMed]
  303. Page, R.L.; Wharton, J.M.; E Wilkinson, W.; Friedman, I.M.; Claypool, W.D.; Karim, A.; Ms, K.G.K.; BS, S.J.M.; Gardiner, P.; Pritchett, E.L.C.; et al. Bidisomide (SC-40230), a new antiarrhythmic agent: Initial study of tolerability and pharmacokinetics. Clin. Pharmacol. Ther. 1992, 51, 371–378. [Google Scholar] [CrossRef] [PubMed]
  304. Alberton, P.; Dex, S.; Popov, C.; Shukunami, C.; Schieker, M.; Docheva, D. Loss of Tenomodulin Results in Reduced Self-Renewal and Augmented Senescence of Tendon Stem/Progenitor Cells. Stem Cells Dev. 2015, 24, 597–609. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  305. Dex, S.; Alberton, P.; Willkomm, L.; Söllradl, T.; Bago, S.; Milz, S.; Shakibaei, M.; Ignatius, A.; Bloch, W.; Clausen-Schaumann, H.; et al. Tenomodulin is Required for Tendon Endurance Running and Collagen I Fibril Adaptation to Mechanical Load. eBioMedicine 2017, 20, 240–254. [Google Scholar] [CrossRef] [Green Version]
  306. Yin, H.; Caceres, M.D.; Yan, Z.; Schieker, M.; Nerlich, M.; Docheva, D. Tenomodulin regulates matrix remodeling of mouse tendon stem/progenitor cells in an ex vivo collagen I gel model. Biochem. Biophys. Res. Commun. 2019, 512, 691–697. [Google Scholar] [CrossRef]
  307. Lewis, J.L.; Krawczak, D.A.; Oegema, T.R.; Westendorf, J.J. Effect of Decorin and Dermatan Sulfate on the Mechanical Properties of a Neocartilage. Connect. Tissue Res. 2010, 51, 159–170. [Google Scholar] [CrossRef]
  308. Dunkman, A.A.; Buckley, M.R.; Mienaltowski, M.J.; Adams, S.M.; Thomas, S.J.; Kumar, A.; Beason, D.P.; Iozzo, R.V.; Birk, D.E.; Soslowsky, L.J. The injury response of aged tendons in the absence of biglycan and decorin. Matrix Biol. 2014, 35, 232–238. [Google Scholar] [CrossRef]
  309. Robinson, K.A.; Sun, M.; Barnum, C.E.; Weiss, S.N.; Huegel, J.; Shetye, S.S.; Lin, L.; Saez, D.; Adams, S.M.; Iozzo, R.V.; et al. Decorin and biglycan are necessary for maintaining collagen fibril structure, fiber realignment, and mechanical properties of mature tendons. Matrix Biol. 2017, 64, 81–93. [Google Scholar] [CrossRef]
  310. Delalande, A.; Gosselin, M.-P.; Suwalski, A.; Guilmain, W.; Leduc, C.; Berchel, M.; Jaffrès, P.-A.; Baril, P.; Midoux, P.; Pichon, C. Enhanced Achilles tendon healing by fibromodulin gene transfer. Nanomed. Nanotechnol. Biol. Med. 2015, 11, 1735–1744. [Google Scholar] [CrossRef]
  311. Nourissat, G.; Berenbaum, F.; Duprez, D. Tendon injury: From biology to tendon repair. Nat. Rev. Rheumatol. 2015, 11, 223–233. [Google Scholar] [CrossRef]
  312. Nakamichi, R.; Asahara, H. Regulation of tendon and ligament differentiation. Bone 2021, 143, 115609. [Google Scholar] [CrossRef]
  313. Goomer, R.S.; Maris, T.M.; Gelberman, R.; Boyer, M.; Silva, M.; Amiel, D. Nonviral In Vivo Gene Therapy for Tissue Engineering of Articular Cartilage and Tendon Repair. Clin. Orthop. Relat. Res. 2000, 379, S189–S200. [Google Scholar] [CrossRef]
  314. Gerich, T.G.; Kang, R.; Fu, F.H.; Robbins, P.D.; Evans, C.H. Gene transfer to the rabbit patellar tendon: Potential for genetic enhancement of tendon and ligament healing. Gene Ther. 1996, 3, 1089–1093. [Google Scholar]
  315. Gerich, T.G.; Kang, R.; Fu, F.H.; Robbins, P.D.; Evans, C.H. Gene transfer to the patellar tendon. Knee Surg. Sports Traumatol. Arthrosc. 1997, 5, 118–123. [Google Scholar] [CrossRef]
  316. Lou, J.; Tu, Y.; Ludwig, F.J.; Zhang, J.; Manske, P.R. Effect of Bone Morphogenetic Protein-12 Gene Transfer on Mesenchymal Progenitor Cells. Clin. Orthop. Relat. Res. 1999, 369, 333–339. [Google Scholar] [CrossRef]
  317. Pascher, A.; Steinert, A.F.; Palmer, G.D.; Betz, O.; Gouze, J.-N.; Gouze, E.; Pilapil, C.; Ghivizzani, S.C.; Evans, C.H.; Murray, M.M. Enhanced Repair of the Anterior Cruciate Ligament by in Situ Gene Transfer: Evaluation in an in Vitro Model. Mol. Ther. 2004, 10, 327–336. [Google Scholar] [CrossRef]
  318. Steinert, A.F.; Weber, M.; Kunz, M.; Palmer, G.D.; Nöth, U.; Evans, C.H.; Murray, M.M. In situ IGF-1 gene delivery to cells emerging from the injured anterior cruciate ligament. Biomaterials 2008, 29, 904–916. [Google Scholar] [CrossRef]
  319. Majewski, M.; Betz, O.; E Ochsner, P.; Liu, F.; Porter, R.M.; Evans, C.H. Ex vivo adenoviral transfer of bone morphogenetic protein 12 (BMP-12) cDNA improves Achilles tendon healing in a rat model. Gene Ther. 2008, 15, 1139–1146. [Google Scholar] [CrossRef] [Green Version]
  320. Wei, X.-L.; Lin, L.; Hou, Y.; Fu, X.; Zhang, J.-Y.; Mao, Z.-B.; Yu, C.-L. Construction of recombinant adenovirus co-expression vector carrying the human transforming growth factor-beta1 and vascular endothelial growth factor genes and its effect on anterior cruciate ligament fibroblasts. Chin. Med. J. 2008, 121, 1426–1432. [Google Scholar] [CrossRef]
  321. Hou, Y.; Mao, Z.; Wei, X.; Lin, L.; Chen, L.; Wang, H.; Fu, X.; Zhang, J.; Yu, C. Effects of transforming growth factor-beta1 and vascular endothelial growth factor 165 gene transfer on Achilles tendon healing. Matrix Biol. 2009, 28, 324–335. [Google Scholar] [CrossRef] [PubMed]
  322. Haddad-Weber, M.; Prager, P.; Kunz, M.; Seefried, L.; Jakob, F.; Murray, M.M.; Evans, C.H.; Nöth, U.; Steinert, A.F. BMP12 and BMP13 gene transfer induce ligamentogenic differentiation in mesenchymal progenitor and anterior cruciate ligament cells. Cytotherapy 2010, 12, 505–513. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  323. Gulotta, L.V.; Kovacevic, D.; Packer, J.D.; Deng, X.H.; Rodeo, S.A. Bone Marrow–Derived Mesenchymal Stem Cells Transduced with Scleraxis Improve Rotator Cuff Healing in a Rat Model. Am. J. Sport. Med. 2011, 39, 1282–1289. [Google Scholar] [CrossRef] [PubMed]
  324. Weber, M.; Kunz, M.; Stehle, J.; Noth, U.; Steinert, A. BMP-12 transduced MSCs in collagen hydrogel for ligament reconstruction. J. Stem Cells Regen. Med. 2007, 2, 72–73. [Google Scholar] [PubMed]
  325. Takayama, K.; Kawakami, Y.; Mifune, Y.; Matsumoto, T.; Tang, Y.; Cummins, J.H.; Greco, N.; Kuroda, R.; Kurosaka, M.; Wang, B.; et al. The effect of blocking angiogenesis on anterior cruciate ligament healing following stem cell transplantation. Biomaterials 2015, 60, 9–19. [Google Scholar] [CrossRef]
  326. Kawakami, Y.; Takayama, K.; Matsumoto, T.; Tang, Y.; Wang, B.; Mifune, Y.; Cummins, J.H.; Warth, R.J.; Kuroda, R.; Kurosaka, M.; et al. Anterior Cruciate Ligament–Derived Stem Cells Transduced with BMP2 Accelerate Graft-Bone Integration After ACL Reconstruction. Am. J. Sport. Med. 2017, 45, 584–597. [Google Scholar] [CrossRef]
  327. Tsutsumi, H.; Kurimoto, R.; Nakamichi, R.; Chiba, T.; Matsushima, T.; Fujii, Y.; Sanada, R.; Kato, T.; Shishido, K.; Sakamaki, Y.; et al. Generation of a tendon-like tissue from human iPS cells. J. Tissue Eng. 2022, 13, 20417314221074018. [Google Scholar] [CrossRef]
  328. Madry, H.; Kohn, D.; Cucchiarini, M. Direct FGF-2 Gene Transfer via Recombinant Adeno-Associated Virus Vectors Stimulates Cell Proliferation, Collagen Production, and the Repair of Experimental Lesions in the Human ACL. Am. J. Sport. Med. 2012, 41, 194–202. [Google Scholar] [CrossRef]
  329. Nakamura, N.; Hart, D.A.; Frank, C.B.; Marchuk, L.L.; Shrive, N.G.; Ota, N.; Taira, K.; Yoshikawa, H.; Kaneda, Y. Efficient Transfer of Intact Oligonucleotides into the Nucleus of Ligament Scar Fibroblasts by HVJ-Cationic Liposomes Is Correlated with Effective Antisense Gene Inhibition. J. Biochem. 2001, 129, 755–759. [Google Scholar] [CrossRef]
  330. Shimomura, T.; Jia, F.; Niyibizi, C.; Woo, S.L. Antisense oligonucleotides reduce synthesis of procollagen alpha1 (V) chain in human patellar tendon fibroblasts: Potential application in healing ligaments and tendons. Connect. Tissue Res. 2003, 44, 167–172. [Google Scholar] [CrossRef]
  331. Groth, K.; Berezhanskyy, T.; Aneja, M.K.; Geiger, J.; Schweizer, M.; Maucksch, L.; Pasewald, T.; Brill, T.; Tigani, B.; Weber, E.; et al. Tendon healing induced by chemically modified mRNAs. Eur. Cells Mater. 2017, 33, 294–307. [Google Scholar] [CrossRef]
  332. Chen, X.-H.; Tong, Y.; Xu, W.-L.; Jin, J.; Qian, W.-B. Expression of telomere binding factor 2 (TRF2) on leukemia cell lines and primary leukemia cells. Zhejiang Da Xue Xue Bao Yi Xue Ban 2008, 37, 170–175. [Google Scholar]
  333. Li, F.; Jia, H.; Yu, C. ACL reconstruction in a rabbit model using irradiated Achilles allograft seeded with mesenchymal stem cells or PDGF-B gene-transfected mesenchymal stem cells. Knee Surg. Sport. Traumatol. Arthrosc. 2007, 15, 1219–1227. [Google Scholar] [CrossRef]
  334. Lu, Y.F.; Liu, Y.; Fu, W.M.; Xu, J.; Wang, B.; Sun, Y.X.; Wu, T.Y.; Xu, L.L.; Chan, K.M.; Zhang, J.F.; et al. Long noncoding RNA H19 accelerates tenogenic differentiation and promotes tendon healing through targeting miR-29b-3p and activating TGF-beta1 signaling. FASEB J. 2017, 31, 954–964. [Google Scholar] [CrossRef] [Green Version]
  335. Lu, P.; Zhang, G.-R.; Cai, Y.-Z.; Heng, B.C.; Ren, H.; Wang, L.-L.; Ji, J.; Zou, X.-H.; Ouyang, H.-W. Lentiviral-Encoded shRNA Silencing of Proteoglycan Decorin Enhances Tendon Repair and Regeneration within a Rat Model. Cell Transplant. 2013, 22, 1507–1517. [Google Scholar] [CrossRef]
  336. Chen, L.; Wang, G.-D.; Liu, J.-P.; Wang, H.-S.; Liu, X.-M.; Wang, Q.; Cai, X.-H. miR-135a modulates tendon stem/progenitor cell senescence via suppressing ROCK1. Bone 2015, 71, 210–216. [Google Scholar] [CrossRef]
  337. Nakamura, N.; Horibe, S.; Matsumoto, N.; Tomita, T.; Natsuume, T.; Kaneda, Y.; Shino, K.; Ochi, T. Transient introduction of a foreign gene into healing rat patellar ligament. J. Clin. Investig. 1996, 97, 226–231. [Google Scholar] [CrossRef] [Green Version]
  338. Nakamura, N.; Shino, K.; Natsuume, T.; Horibe, S.; Matsumoto, N.; Kaneda, Y.; Ochi, T. Early biological effect of in vivo gene transfer of platelet-derived growth factor (PDGF)-B into healing patellar ligament. Gene Ther. 1998, 5, 1165–1170. [Google Scholar] [CrossRef] [Green Version]
  339. Ozkan, I.; Shino, K.; Nakamura, N.; Natsuume, T.; Matsumoto, N.; Horibe, S.; Tomita, T.; Kaneda, Y.; Ochi, T. Direct in vivo gene transfer to healing rat patellar ligament by intra-arterial delivery of haemagglutinating virus of Japan liposomes. Eur. J. Clin. Invest. 1999, 29, 63–67. [Google Scholar] [CrossRef]
  340. Hildebrand, K.A.; Deie, M.; Allen, C.R.; Smith, D.W.; Georgescu, H.I.; Evans, C.H.; Robbins, P.D.; Woo, S.L.-Y. Early expression of marker genes in the rabbit medial collateral and anterior cruciate ligaments: The use of different viral vectors and the effects of injury. J. Orthop. Res. 1999, 17, 37–42. [Google Scholar] [CrossRef]
  341. Menetrey, J.; Kasemkijwattana, C.; Day, C.S.; Bosch, P.; Fu, F.H.; Moreland, M.S.; Huard, J. Direct-, Fibroblast- and Myoblast-Mediated Gene Transfer to the Anterior Cruciate Ligament. Tissue Eng. 1999, 5, 435–442. [Google Scholar] [CrossRef] [PubMed]
  342. Helm, G.A.; Li, J.Z.; Alden, T.D.; Hudson, S.B.; Beres, E.J.; Cunningham, M.; Mikkelsen, M.M.; Pittman, D.D.; Kerns, K.M.; Kallmes, D.F. A light and electron microscopic study of ectopic tendon and ligament formation induced by bone morphogenetic protein—13 adenoviral gene therapy. J. Neurosurg. 2001, 95, 298–307. [Google Scholar] [CrossRef] [PubMed]
  343. Nakamura, N.; Hart, D.A.; Boorman, R.S.; Kaneda, Y.; Shrive, N.G.; Marchuk, L.L.; Shino, K.; Ochi, T.; Frank, C.B. Decorin antisense gene therapy improves functional healing of early rabbit ligament scar with enhanced collagen fibrillogenesis in vivo. J. Orthop. Res. 2000, 18, 517–523. [Google Scholar] [CrossRef] [PubMed]
  344. Herbst, E.; Imhoff, F.B.; Foehr, P.; Milz, S.; Plank, C.; Rudolph, C.; Hasenpusch, G.; Geiger, J.P.; Aneja, M.K.; Groth, K.; et al. Chemically Modified Messenger RNA: Modified RNA Application for Treatment of Achilles Tendon Defects. Tissue Eng. Part A 2019, 25, 113–120. [Google Scholar] [CrossRef] [PubMed]
  345. Nakamura, N.; A Timmermann, S.; A Hart, D.; Kaneda, Y.; Shrive, N.G.; Shino, K.; Ochi, T.; Frank, C.B. A comparison of in vivo gene delivery methods for antisense therapy in ligament healing. Gene Ther. 1998, 5, 1455–1461. [Google Scholar] [CrossRef] [Green Version]
  346. Bez, M.; Kremen, T.; Tawackoli, W.; Avalos, P.; Sheyn, D.; Shapiro, G.; Giaconi, J.C.; Ben David, S.; Snedeker, J.; Gazit, Z.; et al. Ultrasound-Mediated Gene Delivery Enhances Tendon Allograft Integration in Mini-Pig Ligament Reconstruction. Mol. Ther. 2018, 26, 1746–1755. [Google Scholar] [CrossRef] [Green Version]
  347. Martinek, V.; Latterman, C.; Usas, A.; Abramowitch, S.; Woo, S.L.; Fu, F.H.; Huard, J. Enhancement of tendon-bone integration of anterior cruciate ligament grafts with bone morphogenetic protein-2 gene transfer: A histological and biomechanical study. J. Bone Jt. Surg. Am. 2002, 84, 1123–1131. [Google Scholar] [CrossRef] [Green Version]
  348. Wei, X.; Mao, Z.; Hou, Y.; Lin, L.; Xue, T.; Chen, L.; Wang, H.; Yu, C. 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, 204–210. [Google Scholar] [CrossRef]
  349. Schuettrumpf, J.; Zou, J.; Zhang, Y.; Schlachterman, A.; Liu, Y.-L.; Edmonson, S.; Xiao, W.; Arruda, V.R. The inhibitory effects of anticoagulation on in vivo gene transfer by adeno-associated viral or adenoviral vectors. Mol. Ther. 2006, 13, 88–97. [Google Scholar] [CrossRef]
  350. Mangeat, B.; Trono, D. Lentiviral Vectors and Antiretroviral Intrinsic Immunity. Hum. Gene Ther. 2005, 16, 913–920. [Google Scholar] [CrossRef] [Green Version]
  351. Calcedo, R.; Wilson, J.M.M. Humoral Immune Response to AAV. Front. Immunol. 2013, 4, 341. [Google Scholar] [CrossRef] [Green Version]
  352. Fausther-Bovendo, H.; Kobinger, G.P. Pre-existing immunity against Ad vectors: Humoral, cellular, and innate response, what’s important? Hum. Vaccin. Immunother. 2014, 10, 2875–2884. [Google Scholar] [CrossRef]
  353. Ronzitti, G.; Gross, D.; Mingozzi, F. Human Immune Responses to Adeno-Associated Virus (AAV) Vectors. Front. Immunol. 2020, 11, 670. [Google Scholar] [CrossRef]
  354. Goff, S.P. Intracellular trafficking of retroviral genomes during the early phase of infection: Viral exploitation of cellular pathways. J. Gene Med. 2001, 3, 517–528. [Google Scholar] [CrossRef]
  355. Setten, R.L.; Rossi, J.J.; Han, S.-P. The current state and future directions of RNAi-based therapeutics. Nat. Rev. Drug Discov. 2019, 18, 421–446. [Google Scholar] [CrossRef]
  356. Riyad, J.M.; Weber, T. Intracellular trafficking of adeno-associated virus (AAV) vectors: Challenges and future directions. Gene Ther. 2021, 28, 683–696. [Google Scholar] [CrossRef]
  357. Schaffer, D.V.; Koerber, J.T.; Lim, K.-I. Molecular Engineering of Viral Gene Delivery Vehicles. Annu. Rev. Biomed. Eng. 2008, 10, 169–194. [Google Scholar] [CrossRef] [Green Version]
  358. Mitchell, A.M.; Nicolson, S.C.; Warischalk, J.K.; Samulski, R.J. AAV’s anatomy: Roadmap for optimizing vectors for translational success. Curr. Gene Ther. 2010, 10, 319–340. [Google Scholar] [CrossRef]
  359. Kotterman, M.A.; Schaffer, D.V. Engineering adeno-associated viruses for clinical gene therapy. Nat. Rev. Genet. 2014, 15, 445–451. [Google Scholar] [CrossRef] [Green Version]
  360. Kotterman, M.A.; Chalberg, T.W.; Schaffer, D.V. Viral Vectors for Gene Therapy: Translational and Clinical Outlook. Annu. Rev. Biomed. Eng. 2015, 17, 63–89. [Google Scholar] [CrossRef] [Green Version]
  361. Rabinowitz, J.; Chan, Y.K.; Samulski, R.J. Adeno-Associated Virus (AAV) Versus Immune Response. Viruses 2019, 11, 102. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  362. Patel, S.; Athirasala, A.; Menezes, P.P.; Ashwanikumar, N.; Zou, T.; Sahay, G.; Bertassoni, L.E. Messenger RNA Delivery for Tissue Engineering and Regenerative Medicine Applications. Tissue Eng. Part A 2019, 25, 91–112. [Google Scholar] [CrossRef] [PubMed]
  363. Kavanagh, E.W.; Green, J.J. Toward Gene Transfer Nanoparticles as Therapeutics. Adv. Health Mater. 2022, 11, e2102145. [Google Scholar] [CrossRef] [PubMed]
  364. Langer, R.S.; Peppas, N.A. Present and future applications of biomaterials in controlled drug delivery systems. Biomaterials 1981, 2, 201–214. [Google Scholar] [CrossRef]
  365. Langer, R.; Vacanti, J.P. Tissue engineering. Science 1993, 260, 920–926. [Google Scholar] [CrossRef] [Green Version]
  366. Weiser, J.R.; Saltzman, W.M. Controlled release for local delivery of drugs: Barriers and models. J. Control. Release 2014, 190, 664–673. [Google Scholar] [CrossRef] [Green Version]
  367. Alvarez-Lorenzo, C.; Concheiro, A. Smart drug delivery systems: From fundamentals to the clinic. Chem. Commun. 2014, 50, 7743–7765. [Google Scholar] [CrossRef] [Green Version]
  368. Mitragotri, S.; Burke, P.A.; Langer, R. Overcoming the challenges in administering biopharmaceuticals: Formulation and delivery strategies. Nat. Rev. Drug Discov. 2014, 13, 655–672. [Google Scholar] [CrossRef] [Green Version]
  369. Adepu, S.; Ramakrishna, S. Controlled Drug Delivery Systems: Current Status and Future Directions. Molecules 2021, 26, 5905. [Google Scholar] [CrossRef]
  370. Bonadio, J.; Smiley, E.; Patil, P.; Goldstein, S. Localized, direct plasmid gene delivery in vivo: Prolonged therapy results in reproducible tissue regeneration. Nat. Med. 1999, 5, 753–759. [Google Scholar] [CrossRef]
  371. Evans, C.H.; Robbins, P.D. Genetically Augmented Tissue Engineering of the Musculoskeletal System. Clin. Orthop. Relat. Res. 1999, 367, S410–S418. [Google Scholar] [CrossRef]
  372. Bonadio, J.; A Goldstein, S.; Levy, R.J. Gene therapy for tissue repair and regeneration. Adv. Drug Deliv. Rev. 1998, 33, 53–69. [Google Scholar] [CrossRef]
  373. Bonadio, J. Tissue engineering via local gene delivery. Klin. Wochenschr. 2000, 78, 303–311. [Google Scholar]
  374. Bonadio, J. Tissue engineering via local gene delivery: Update and future prospects for enhancing the technology. Adv. Drug Deliv. Rev. 2000, 44, 185–194. [Google Scholar] [CrossRef]
  375. Jang, J.-H.; Houchin, T.L.; Shea, L.D. Gene delivery from polymer scaffolds for tissue engineering. Expert Rev. Med. Devices 2004, 1, 127–138. [Google Scholar] [CrossRef]
  376. De Laporte, L.; Shea, L.D. Matrices and scaffolds for DNA delivery in tissue engineering. Adv. Drug Deliv. Rev. 2007, 59, 292–307. [Google Scholar] [CrossRef] [Green Version]
  377. Evans, C.H.; Ghivizzani, S.C.; Robbins, P.D. Orthopedic Gene Therapy in 2008. Mol. Ther. 2009, 17, 231–244. [Google Scholar] [CrossRef]
  378. Evans, C.H. Advances in Regenerative Orthopedics. Mayo Clin. Proc. 2013, 88, 1323–1339. [Google Scholar] [CrossRef] [Green Version]
  379. Gower, R.M.; Shea, L.D. Biomaterial Scaffolds for Controlled, Localized Gene Delivery of Regenerative Factors. Adv. Wound Care 2013, 2, 100–106. [Google Scholar] [CrossRef] [Green Version]
  380. Smith, B.D.; Grande, D.A. The current state of scaffolds for musculoskeletal regenerative applications. Nat. Rev. Rheumatol. 2015, 11, 213–222. [Google Scholar] [CrossRef]
  381. Evans, C.H.; Huard, J. Gene therapy approaches to regenerating the musculoskeletal system. Nat. Rev. Rheumatol. 2015, 11, 234–242. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  382. Lee, K.; Silva, E.A.; Mooney, D.J. Growth factor delivery-based tissue engineering: General approaches and a review of recent developments. J. R. Soc. Interface 2011, 8, 153–170. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  383. Liechty, W.B.; Kryscio, D.R.; Slaughter, B.V.; Peppas, N.A. Polymers for drug delivery systems. Annu. Rev. Chem. Biomol. Eng. 2010, 1, 149–173. [Google Scholar] [CrossRef] [PubMed]
  384. Zhou, Y.; Zhu, C.; Wu, Y.F.; Zhang, L.; Tang, J.B. Effective modulation of transforming growth factor-beta1 expression through engineered microRNA-based plasmid-loaded nanospheres. Cytotherapy 2015, 17, 320–329. [Google Scholar] [CrossRef] [PubMed]
  385. Qin, J.; Hou, Z.-Q.; Wang, H.; Wang, X.-L.; Liu, Y.-Y.; Gao, X.-H.; Lin, Y.-J.; Huang, B.-H. Effects of gene-activated matrix on autograft healing of anterior cruciate ligament. Mol. Med. Rep. 2013, 7, 679–683. [Google Scholar] [CrossRef] [Green Version]
  386. Wu, G.; Sun, B.; Zhao, C.; Wang, Z.; Teng, S.; Yang, M.; Cui, Z.; Zhu, G.; Yu, Y. Three-dimensional tendon scaffold loaded with TGF-beta1 gene silencing plasmid prevents tendon adhesion and promotes tendon repair. ACS Biomater. Sci. Eng. 2021, 7, 5739–5748. [Google Scholar] [CrossRef]
  387. Basile, P.; Dadali, T.; Jacobson, J.; Hasslund, S.; Ulrich-Vinther, M.; Søballe, K.; Nishio, Y.; Drissi, M.H.; Langstein, H.N.; Mitten, D.J.; et al. Freeze-dried Tendon Allografts as Tissue-engineering Scaffolds for Gdf5 Gene Delivery. Mol. Ther. 2008, 16, 466–473. [Google Scholar] [CrossRef]
  388. Hasslund, S.; Dadali, T.; Ulrich-Vinther, M.; Søballe, K.; Schwarz, E.M.; A Awad, H. Freeze-dried allograft-mediated gene or protein delivery of growth and differentiation factor 5 reduces reconstructed murine flexor tendon adhesions. J. Tissue Eng. 2014, 5, 2041731414528736. [Google Scholar] [CrossRef]
  389. Shoji, T.; Nakasa, T.; Yamasaki, K.; Kodama, A.; Miyaki, S.; Niimoto, T.; Okuhara, A.; Kamei, N.; Adachi, N.; Ochi, M. The Effect of Intra-articular Injection of MicroRNA-210 on Ligament Healing in a Rat Model. Am. J. Sport. Med. 2012, 40, 2470–2478. [Google Scholar] [CrossRef]
  390. Usman, M.A.; Nakasa, T.; Shoji, T.; Kato, T.; Kawanishi, Y.; Hamanishi, M.; Kamei, N.; Ochi, M. The effect of administration of double stranded MicroRNA-210 on acceleration of Achilles tendon healing in a rat model. J. Orthop. Sci. 2015, 20, 538–546. [Google Scholar] [CrossRef]
  391. Sakti, M.; Nakasa, T.; Shoji, T.; Usman, M.A.; Kawanishi, Y.; Hamanishi, M.; Yusuf, I.; Ochi, M. Acceleration of healing of the medial collateral ligament of the knee by local administration of synthetic microRNA-210 in a rat model. Asia-Pac. J. Sport. Med. Arthrosc. Rehabil. Technol. 2015, 2, 129–136. [Google Scholar] [CrossRef] [Green Version]
  392. Ginn, S.L.; Amaya, A.K.; Alexander, I.E.; Edelstein, M.; Abedi, M.R. Gene therapy clinical trials worldwide to 2017: An update. J. Gene Med. 2018, 20, e3015. [Google Scholar] [CrossRef]
  393. Evans, C.H.; Ghivizzani, S.C.; Robbins, P.D. Arthritis gene therapy is becoming a reality. Nat. Rev. Rheumatol. 2018, 14, 381–382. [Google Scholar] [CrossRef]
  394. Watson-Levings, R.S.; Palmer, G.D.; Levings, P.P.; Dacanay, E.A.; Evans, C.H.; Ghivizzani, S.C. Gene Therapy in Orthopaedics: Progress and Challenges in Pre-Clinical Development and Translation. Front. Bioeng. Biotechnol. 2022, 10, 901317. [Google Scholar] [CrossRef]
  395. Murphy, S.V.; Atala, A. 3D bioprinting of tissues and organs. Nat. Biotechnol. 2014, 32, 773–785. [Google Scholar] [CrossRef]
  396. Park, S.H.; Choi, Y.-J.; Moon, S.W.; Lee, B.H.; Shim, J.-H.; Cho, D.-W.; Wang, J.H. Three-Dimensional Bio-Printed Scaffold Sleeves with Mesenchymal Stem Cells for Enhancement of Tendon-to-Bone Healing in Anterior Cruciate Ligament Reconstruction Using Soft-Tissue Tendon Graft. Arthrosc. J. Arthrosc. Relat. Surg. 2018, 34, 166–179. [Google Scholar] [CrossRef]
  397. Cunniffe, G.M.; Gonzalez-Fernandez, T.; Daly, A.; Sathy, B.N.; Jeon, O.; Alsberg, E.; Kelly, D. Three-Dimensional Bioprinting of Polycaprolactone Reinforced Gene Activated Bioinks for Bone Tissue Engineering. Tissue Eng. Part A 2017, 23, 891–900. [Google Scholar] [CrossRef]
  398. Potyondy, T.; Uquillas, J.A.; Tebon, P.J.; Byambaa, B.; Hasan, A.; Tavafoghi, M.; Mary, H.; Aninwene, G.E., 2nd; Pountos, I.; Khademhosseini, A.; et al. Recent advances in 3D bioprinting of musculoskeletal tissues. Biofabrication 2021, 13, 022001. [Google Scholar] [CrossRef]
  399. Bakirci, E.; Guenat, O.; Ahmad, S.; Gantenbein, B. Tissue engineering approaches for the repair and regeneration of the anterior cruciate ligament: Towards 3D bioprinted ACL-on-chip. Eur. Cells Mater. 2022, 44, 21–42. [Google Scholar] [CrossRef]
  400. Perez-Pinera, P.; Kocak, D.D.; Vockley, C.M.; Adler, A.F.; Kabadi, A.M.; Polstein, L.R.; Thakore, P.I.; Glass, K.A.; Ousterout, D.G.; Leong, K.W.; et al. RNA-guided gene activation by CRISPR-Cas9–based transcription factors. Nat. Methods 2013, 10, 973–976. [Google Scholar] [CrossRef] [Green Version]
  401. Almarza, D.; Cucchiarini, M.; Loughlin, J. Genome editing for human osteoarthritis—A perspective. Osteoarthr. Cartil. 2017, 25, 1195–1198. [Google Scholar] [CrossRef] [PubMed]
  402. Brunger, J.M.; Zutshi, A.; Willard, V.P.; Gersbach, C.A.; Guilak, F. CRISPR/Cas9 Editing of Murine Induced Pluripotent Stem Cells for Engineering Inflammation-Resistant Tissues. Arthritis Rheumatol. 2017, 69, 1111–1121. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  403. Brunger, J.M.; Zutshi, A.; Willard, V.P.; Gersbach, C.A.; Guilak, F. Genome Engineering of Stem Cells for Autonomously Regulated, Closed-Loop Delivery of Biologic Drugs. Stem Cell Rep. 2017, 8, 1202–1213. [Google Scholar] [CrossRef] [PubMed]
  404. Choi, Y.-R.; Collins, K.H.; Lee, J.-W.; Kang, H.-J.; Guilak, F. Genome Engineering for Osteoarthritis: From Designer Cells to Disease-Modifying Drugs. Tissue Eng. Regen. Med. 2019, 16, 335–343. [Google Scholar] [CrossRef]
  405. Choi, Y.-R.; Collins, K.H.; Springer, L.E.; Pferdehirt, L.; Ross, A.K.; Wu, C.-L.; Moutos, F.T.; Harasymowicz, N.S.; Brunger, J.M.; Pham, C.T.N.; et al. A genome-engineered bioartificial implant for autoregulated anticytokine drug delivery. Sci. Adv. 2021, 7, eabj1414. [Google Scholar] [CrossRef]
  406. Doudna, J.A.; Charpentier, E. The new frontier of genome engineering with CRISPR-Cas9. Science 2014, 346, 1258096. [Google Scholar] [CrossRef]
  407. Farhang, N.; Brunger, J.M.; Stover, J.D.; Thakore, P.I.; Lawrence, B.; Guilak, F.; Gersbach, C.A.; Setton, L.A.; Bowles, R.D. CRISPR-Based Epigenome Editing of Cytokine Receptors for the Promotion of Cell Survival and Tissue Deposition in Inflammatory Environments. Tissue Eng. Part A 2017, 23, 738–749. [Google Scholar] [CrossRef]
  408. Guilak, F.; Pferdehirt, L.; Ross, A.K.; Choi, Y.; Collins, K.H.; Nims, R.J.; Katz, D.B.; Klimak, M.; Tabbaa, S.; Pham, C.T.N. Designer Stem Cells: Genome Engineering and the Next Generation of Cell-Based Therapies. J. Orthop. Res. 2019, 37, 1287–1293. [Google Scholar] [CrossRef]
  409. Klimak, M.; Nims, R.J.; Pferdehirt, L.; Collins, K.H.; Harasymowicz, N.S.; Oswald, S.J.; Setton, L.A.; Guilak, F. Immunoengineering the next generation of arthritis therapies. Acta Biomater. 2021, 133, 74–86. [Google Scholar] [CrossRef]
Ijms 23 14467 g001 550
Figure 1. Knee key ligaments (anterior cruciate ligament—ACL, posterior cruciate ligament—PCL, medial collateral ligament—MCL, lateral collateral ligament—LCL).
Figure 1. Knee key ligaments (anterior cruciate ligament—ACL, posterior cruciate ligament—PCL, medial collateral ligament—MCL, lateral collateral ligament—LCL).
Ijms 23 14467 g001
Ijms 23 14467 g002 550
Figure 2. Schematic drawing of the multi-unit hierarchical structure of the ligament.
Figure 2. Schematic drawing of the multi-unit hierarchical structure of the ligament.
Ijms 23 14467 g002
Ijms 23 14467 g003 550
Figure 3. Expression patterns of critical transcription factors during the development of the ACL (SCX, scleraxis; FGF, fibroblast growth factor; TGF-β, transforming growth factor beta; MKX, Mohawk, Egr1, early growth response factor 1).
Figure 3. Expression patterns of critical transcription factors during the development of the ACL (SCX, scleraxis; FGF, fibroblast growth factor; TGF-β, transforming growth factor beta; MKX, Mohawk, Egr1, early growth response factor 1).
Ijms 23 14467 g003
Table
Table 1. Applications of tissue engineering for ACL repair.
Table 1. Applications of tissue engineering for ACL repair.
ScaffoldsCellsFactorsBioreactorsEffectsRefs.
fibrin---improved ACL repair
(goats)		[150]
CTGF-improved ACL repair
(rabbits)		[151]
HA---improved ACL repair
(rabbits, patients)		[152,155]
TGF-β, FGF-2,
PDGF, insulin		-higher cell outgrowth
in ACL explants		[154]
MSCs--higher cell growth,
differentiation		[153]
chitosanACL fibroblasts--higher cell adhesion,
differentiation		[156]
collagen---improved ACL repair
(rabbits, pigs)		[157,158,161,162,164]
ACL,
skin fibroblasts
--higher cell growth,
differentiation		[159,160,166,168]
MSCs-+higher cell growth,
differentiation,
improved ACL repair
(rabbits)		[44,163,167]
ASCs--higher cell growth,
differentiation		[165]
silk---improved ACL repair
(pigs, goats)		[179,180]
ACL,
skin fibroblasts		--higher cell growth,
differentiation,
improved ACL repair
(dogs)		[171,178,182]
MSCs--higher cell growth,
differentiation,
improved ACL repair
(sheep)		[169,171,173,174,175,176,177,179,181,183]
+higher cell growth,
differentiation		[170]
TGF-β, FGF-2,
EGF		-higher cell growth,
differentiation		[172]
PGA---improved ACL repair
(dogs)		[185]
ACL fibroblasts--higher cell growth,
differentiation		[184,186]
PLAACL fibroblasts--higher cell growth,
differentiation		[186,188,189,194]
MSCs--higher cell growth,
differentiation		[190,194]
PLGAACL,
skin fibroblasts		--higher cell growth,
differentiation		[168,186,188,196]
MSCs--higher cell growth,
differentiation		[196,197]
TGF-β, GDF-5-higher cell growth,
differentiation		[198]
PCL-FGF-2-improved ACL repair
(rats)		[203]
ACL fibroblasts--higher cell growth,
differentiation		[200,204,205,206]
MSCs-+higher cell growth,
differentiation		[201]
FGF-2+higher cell growth,
differentiation		[199]
PUACL fibroblasts--higher cell growth,
differentiation		[168]
OPFMSCs +higher cell growth,
differentiation		[207]
PET---tissue integration
(sheep)		[211]
ACL fibroblasts--higher cell growth,
differentiation		[209]
collagen/GAGACL explants--higher cell migration,
differentiation		[213,214]
collagen/silk---improved ACL repair
(rabbits)		[215,216,217]
collagen/p(DTD DD)---improved ACL repair
(sheep)		[218]
collagen/PRP---improved ACL repair
(dogs, pigs)		[164,225,226,227,228]
ACL fibroblasts--higher cell growth,
differentiation		[229]
silk/PLGAMSCsFGF-2-higher cell growth,
differentiation		[219]
chitosan/HA---improved ACL repair
(rats)		[220]
chitosan/PLAACL fibroblasts--higher cell growth,
differentiation		[221]
chitosan/PCLACL fibroblasts--higher cell growth,
differentiation		[222]
PLA/PCLMSCs--higher cell growth,
differentiation		[223]
PGA/PCLACL fibroblasts--higher cell growth,
differentiation		[184]
PLA/PLGAMSCs--improved ACL repair
(rabbits)		[224]
Abbreviations: HA, hyaluronic acid; PGA, poly(glycolic acid); PLA, poly(lactic acid); PLGA, poly(lactic-co-glycolic acid); PCL, poly(caprolactone); PU, polyurethane; OPF, oligo(poly(ethylene glycol) fumarate); PET, poly(ethylene terephthalate); GAG, glycosaminoglycan; p(DTD DD), poly(desaminotyrosyl-tyrosine dodecyl dodecanedioate); PRP, platelet-rich plasma; MSCs, bone marrow-derived mesenchymal stromal cells; ACL, anterior cruciate ligament; ASCs, adipose-derived MSCs; CTGF, connective tissue growth factor; TGF-β, transforming growth factor beta; FGF-2, basic fibroblast growth factor; PDGF, platelet-derived growth factor; EGF, epidermal growth factor; GDF-5, growth differentiation factor 5.
Table
Table 2. Gene transfer vectors.
Table 2. Gene transfer vectors.
VectorsIntegrationAdvantagesLimitations
TypeClass
nonviral
vectors		no. large capacity
. cost effectiveness
. no infectiosity/replication
. no toxicity/immunogenicity
  • low efficacy
  • short-term expression
  • only dividing cells
viral
vectors		adenoviralno. large capacity
. high efficacy
. dividing/quiescent cells		. short-term expression
. toxicity/immunogenicity
HSVno. large capacity
. high efficacy
. dividing/quiescent cells		. short-term expression
. toxicity/immunogenicity
retroviralyes. large capacity
. long-term expression		. low efficacy without selection
. only dividing cells
. toxicity/immunogenicity
. potential insertional mutagenesis
lentiviralyes. large capacity
. dividing/quiescent cells
. long-term expression		. low efficacy without selection
. toxicity/immunogenicity
. potential insertional mutagenesis
. HIV material
rAAVno. high efficacy
. dividing/quiescent cells
. long-term expression		. small capacity
. possible immunogenicity
. potential insertional mutagenesis
Abbreviations: HSV, herpes simplex viral vector; rAAV, recombinant adeno-associated viral vectors; HIV, human immunodeficiency virus.
Table
Table 3. Applications of classical gene therapy for ACL repair in vitro and in situ.
Table 3. Applications of classical gene therapy for ACL repair in vitro and in situ.
VectorsCell TargetsGenesEffectsRefs.
nonviral
vectors		rabbit ligament cellsODN
(decorin)		suppression of decorin
expression (one day)		[329]
human tendon cellsODN
(TVPα1)		suppression of TVPα1
expression (one day)		[330]
horse, bovine, sheep,
pig, rat tendons		mRNA
(lacZ, luc, BMP-7)		effective gene expression
(one day)		[331]
rabbit perichondrial cellslacZ, TGF-βeffective gene expression
(2 days)		[313]
adenoviral
vectors		rabbit ACL cellslacZ, TGF-β, VEGFeffective gene expression, high DNA, type-I/-III collagen, FN contents (3 days)[314,315,320]
bovine ACL cellsGFP, luc, TGF-β
(type-I collagen gel)		effective gene expression (6 days), high DNA and type-I/-III collagen contents (3 weeks)[317]
human ACL cellsGFP, luc,
BMP-12, -13, IGF-I
(type-I collagen gel)		effective gene expression, high DNA, type-I/-III collagen, tenascin, TNMD, elastin, vimentin, decorin, FN, biglycan, SCX contents (3 weeks)[318,322]
murine MSC lineBMP-12effective gene expression
(5 days)		[316,332]
rat MSCsSCXeffective gene expression
(one day)		[323]
rabbit MSCsTGF-β, VEGFeffective gene expression
(2 days)		[321]
human MSCsBMP-12, -13
(type-I collagen gel)		effective gene expression
(2 weeks), high DNA, type-III collagen, tenascin, TNMD, elastin, vimentin, decorin, FN, biglycan, SCX contents (3 weeks)		[322,324]
SCX, MKXeffective gene expression, high type-I collagen, tenascin, TNMD contents (one week)[282]
retroviral
vectors		rabbit ACL cellslacZeffective gene expression
(one week)		[314,315]
murine MSC lineMKXhigh type-I collagen, decorin contents (5 days)[283]
rabbit MSCsPDGFeffective gene expression
(12 weeks)		[333]
human tendon-derived stem cellslncRNA
(H19)		enhanced tenogenic
differentiation (one week)		[334]
lentiviral
vectors		rat tendon cellsshRNA
(decorin)		suppression of decorin
expression (3 days)		[335]
rat ACL-derived
stem cells		VEGFeffective gene expression
(2 days)		[325]
rat tendon-derived
stem cells		miRNA
(ROCK1)		high tenogenic differentiation (one week)[336]
human MSCsSCXeffective gene expression, high type-I collagen, TNMD, decorin, FN, fibromodulin, lumican, α-SMA contents
(cell selection)		[275]
human ACL-derived
stem cells		BMP-2effective gene expression
(3 days)		[326]
human iPSCsMKXhigh type-III collagen, decorin, fibromodulin, SCX contents (cell selection)[327]
rAAV
vectors		human ACL cells,
explants (normal, torn)		lacZ, FGF-2effective gene expression, high DNA, type-I/-III collagen, SCX, α-SMA, NF-κB contents
(one month)		[328]
Abbreviations: rAAV, recombinant adeno-associated viral vectors; ACL, anterior cruciate ligament; MSCs, mesenchymal stromal cells; iPSCs, induced pluripotent stem cells; ODN, oligodeoxyribonucleotide; TVPα1, type V procollagen α1 chain; mRNA, messenger ribonucleic acid; lacZ, β-galactosidase; luc, luciferase; BMP, bone morphogenetic protein; TGF-β, transforming growth factor beta; VEGF, vascular endothelial growth factor; GFP, green fluorescent protein; IGF-I, insulin-like growth factor I; SCX, scleraxis; MKX, Mohawk; PDGF, platelet-derived growth factor; lncRNA, long non-coding RNA (H19 involved in TGF-β signaling); shRNA, short hairpin RNA; miRNA, microRNA; ROCK1, Rho-associated coiled-coil protein kinase 1; FGF-2, basic fibroblast growth factor; DNA, deoxyribonucleic acid; TNMD; tenomodulin; FN, fibronectin; α-SMA, alpha-smooth muscle actin; NF-κB, nuclear factor kappa B.
Table
Table 4. Applications of classical gene therapy for direct ACL repair in vivo.
Table 4. Applications of classical gene therapy for direct ACL repair in vivo.
VectorsAnimal ModelsGenesEffectsRefs.
nonviral
vectors		rat ligament
lesion		lacZ, PDGFeffective gene expression, high type-I collagen deposition (4 weeks)[337,338,339]
ODN
(decorin)		suppression of decorin expression (4 weeks), high type-I collagen deposition with stronger mechanical properties (6 weeks)[338,343]
rat, sheep tendon
injury		mRNA
(BMP-7)		effective gene expression, high type-III collagen deposition (one week)[331]
adenoviral
vectors		rat ligament
lesion		BMP-13high collagen deposition, neoligament
formation (14 weeks)		[342]
rabbit ligament
lesion		lacZeffective gene expression
(2 weeks; 6 weeks at very high vector dose)		[340,341]
-rat tendon
injury		mRNA
(FGF-2)		effective gene expression,
stronger mechanical properties (2 weeks)		[344]
Abbreviations: lacZ, β-galactosidase; PDGF, platelet-derived growth factor; ODN, oligodeoxyribonucleotide; mRNA, messenger ribonucleic acid; BMP-7, bone morphogenetic protein 7; FGF-2, basic fibroblast growth factor.
Table
Table 5. Applications of classical gene therapy for indirect ACL repair ex vivo.
Table 5. Applications of classical gene therapy for indirect ACL repair ex vivo.
VectorsAnimal ModelsCellsGenesEffectsRefs.
nonviral
vectors		minipig ACL
lesion		ACL graftGFP, BMP-6effective gene expression
(2 weeks), ACL repair with stronger mechanical
properties (8 weeks)		[346]
adenoviral
vectors		mouse ectopic
injection
(muscle)		murine MSC lineBMP-12high collagen deposition,
neoligament
formation (4 weeks)		[316]
rabbit ligament
lesion		rabbit ACL cellslacZeffective gene
expression (2 weeks)		[341]
rabbit ACL
lesion		rabbit MSCsTGF-β, VEGFACL remodeling with stronger mechanical
properties (24 weeks)		[348]
rabbit tendon graftlacZ, BMP-2effective gene expression (2 weeks), high collagen
deposition with stronger
mechanical properties
(8 weeks)		[347]
retroviral
vectors		rabbit ligament
lesion		rabbit ACL cellslacZeffective gene
expression (10 days)		[340]
rabbit MSCsPDGFhigh collagen deposition,
ligament remodeling
(12 weeks)		[333]
mouse tendon
injury		human tendon-derived stem cellslncRNA
(H19)		high type-I collagen deposition, TNMD, decorin contents (4 weeks)[334]
lentiviral
vectors		rat ACL
lesion		human ACL-derived
stem cells		BMP-2high type-I/-III collagen deposition, α-SMA contents,
ACL repair (8 weeks)		[326]
rat ACL-derived
stem cells		VEGFhigh type-I collagen deposition, ligament remodeling with stronger mechanical properties (4 weeks)[325]
rat tendon
injury		rat tendon cellsshRNA
(decorin)		high collagen deposition
(4 weeks)		[335]
Abbreviations: ACL, anterior cruciate ligament; MSCs, mesenchymal stromal cells; GFP, green fluorescent protein; BMP, bone morphogenetic protein; lacZ, β-galactosidase; TGF-β, transforming growth factor beta; VEGF, vascular endothelial growth factor; PDGF, platelet-derived growth factor; lncRNA, long non-coding RNA (H19 involved in TGF-β signaling); shRNA, short hairpin RNA; α-SMA, alpha-smooth muscle actin.
Table
Table 6. Applications of biomaterial-guided gene therapy for ACL repair.
Table 6. Applications of biomaterial-guided gene therapy for ACL repair.
Animal ModelsVectorsCell TargetsGenesBiomaterialsEffectsRefs.
-nonviral
vectors		chicken tendon cellsGFP, miRNA (TGF-β)PLGA
nanospheres		effective gene expression (GFP), suppression of TGF-β expression (miRNA TGF-β)
(3 weeks)		[384]
adenoviral
vectors		bovine ACL cellsGFPtype-I
collagen gel		effective gene
expression (3 weeks)		[317]
bovine ACL explants (torn)TGF-βtype-I
collagen gel		effective gene expression, high type-I/-III deposition,
ACL repair (4 weeks)		[317]
human ACL explants (torn)GFP, IGF-Itype-I
collagen gel		effective gene expression, high DNA
contents (IGF-I)
(3 weeks)		[318]
rabbit ACL
lesion		nonviral
vectors		-TGF-βtendon grafthigh collagen deposition, wound healing with stronger
mechanical properties
(6 months)		[385]
chicken tendon
injury		nonviral
vectors		-miRNA (TGF-β)PLGA
nanospheres, 3DB
composite (PCL, PDA NPs, gelatin, HA, alginate)		suppression of TGF-β expression, wound healing (6 weeks)[384,386]
rat tendon
injury		adenoviral
vectors		-BMP-12muscle grafthigh collagen deposition, wound healing (4 weeks)[319]
lentiviral
vectors		-shRNA (decorin)tendon grafthigh collagen deposition, wound healing (4 weeks)[335]
mouse tendon
injury		rAAV
vectors		-luc, GDF-5tendon grafteffective gene expression, wound healing with stronger
mechanical properties
(2–3 weeks)		[387,388]
rat ACL lesion,
tendon injury		--miRNA
(angiogenic miR-210)		type-I
collagen gel		high type-I collagen deposition, VEGF expression, wound healing with stronger mechanical properties (4–12 weeks)[389,390,391]
Abbreviations: ACL, anterior cruciate ligament; rAAV, recombinant adeno-associated viral vectors; GFP, green fluorescent protein; miRNA, microRNA; TGF-β, transforming growth factor beta; IGF-I, insulin-like growth factor I; BMP-12, bone morphogenetic protein 12; shRNA, short hairpin RNA; GDF-5, growth differentiation factor 5; luc, luciferase; PLGA, polylactic-co-glycolic acid; PCL, polycaprolactone; PDA NPs, polydopamine nanoparticles; HA, hyaluronic acid; VEGF, vascular endothelial growth factor.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Amini, M.; Venkatesan, J.K.; Liu, W.; Leroux, A.; Nguyen, T.N.; Madry, H.; Migonney, V.; Cucchiarini, M. Advanced Gene Therapy Strategies for the Repair of ACL Injuries. Int. J. Mol. Sci. 2022, 23, 14467. https://doi.org/10.3390/ijms232214467

AMA Style

Amini M, Venkatesan JK, Liu W, Leroux A, Nguyen TN, Madry H, Migonney V, Cucchiarini M. Advanced Gene Therapy Strategies for the Repair of ACL Injuries. International Journal of Molecular Sciences. 2022; 23(22):14467. https://doi.org/10.3390/ijms232214467

Chicago/Turabian Style

Amini, Mahnaz, Jagadeesh K. Venkatesan, Wei Liu, Amélie Leroux, Tuan Ngoc Nguyen, Henning Madry, Véronique Migonney, and Magali Cucchiarini. 2022. "Advanced Gene Therapy Strategies for the Repair of ACL Injuries" International Journal of Molecular Sciences 23, no. 22: 14467. https://doi.org/10.3390/ijms232214467

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop