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Tendon to Fibrocartilage Metaplasia

- See:
       - autologous hamstring resurfacing arthroplasty and the main cartilage menu;
       - enhanced microfracture articles


It may turn out the most overlooked resource for matrix induced chondrogenesis is autologous hamstring tendons.
These tendons are easy to harvest, have minimal morbidity, and like other tendons, are preprogrammed to
transform into fibrocartilage when subjected to compression.  The science on tendon to fibrocartilage metaplasia is
well written and complete.  Far from being an inert scaffold, tendons are complex structures capable of compositional
adaptations, and suited to different biomechanical roles.  When tendons are placed under compressive loads, a subpopulation
of tenoblast progenitor cells proliferate and produce an extracellular matrix containing type II collagens and proteoglycans 
(fibrocartilage). (ref)  That is, repeated hydrostatic stresses cause a cellular differentiation pathway that is chondrocytic in nature. (ref)
It is important to point out that this metaplasia phenomena is not some unusual evolutionary quirk, but rather a precise and sophisticated
process in which fibrocartilage is deposited within fascicles allowing them to slide, and produces an ability to withstand compression. (ref)

By rigidly opposing the hamstring tendons against the microfractured surface of the medial femoral condyle, we expect
much more than an inert collagen scaffold, but rather an active partner in helping to foster a new viable fibrocartilage surface.
Instead of going to extra-ordinary lengths to develop a biologically compatible artificial matrix, we have a readily
available pair of tendons that meet all of the criteria listed by a recent academy review article:

"The characteristics that make scaffolds optimal for clinical use are that they be bio compatible, biodegradable, 
permeable, reproducible, mechanically stable, non cytotoxic, and capable of serving as a temporary support for the 
cells while allowing for eventual replacement by matrix components synthesized by the implanted cells." (The use of scaffolds in the management of articular cartilage injury.)

Fibrocartilage in tendons and ligaments--an adaptation to compressive load.

References for Tendon Metaplasia:

            - Mechanobiology of tendon adaptation to compressive loading through fibrocartilaginous metaplasia
            - Cartilage Differentiation and Growth
            - Tendon injuries: basic science and clinical medicine
            - The development of sites of metaplastic change in regenerating tendon 
            - Trace elements in human tendons and ligaments 
            - Cellular shape and pressure may mediate mechanical control of tissue composition in tendons.
            - Gene regulation ex vivo within a wrap-around tendon.
            - Interface healing between remaining patella and patellar tendonafter partial patellectomy-an experimental study in rabbits
            - Influence of Cyclic Hydrostatic Pressure on Fibrocartilaginous Metaplasia of Achilles Tendon Fibroblasts
            - Anisotropic Poro-Hyperelastic Constitutive Models for Soft Connective Tissues: Study of Age and Stress Modulated Fibrocartilage Metaplasia in Tendons 
            - Cartilaginous Metaplasia of Connective Tissue in Clinical Skin Arthroplasty
            - Tendon Development and Fibrocartilage Metaplasia
            - Fibrocartilage in tendons and ligaments — an adaptation to compressive load
            - Development and Evolutionary Skeletal Biology
            - Induction of Transdifferentiation in Pellet Cultured Tenocytes to Cartilaginous Phenotype under Cyclic Hydrostatic Pressure
            - Histological study of resection arthroplasty with and without tendon ball interposition in dogs.
            - Healing Compared Between Bone to Tendon and Cartilage to Tendon in a Partial Inferior Patellectomy Model in Rabbits
            - Development of functionally distinct fibrocartilages at two sites in the quadriceps tendon of the rat: the suprapatella and the attachment to the patella
            - Partial patellectomy induces a decrease in the proteoglycan content in the remaining patellar articular cartilage. An experimental study in rabbits
            - Observations on the mechanically induced differentiation of cartilage from fibrous connective tissue.
            - Healing Compared Between Bone to Tendon and Cartilage to Tendon in a Partial Inferior Patellectomy Model in Rabbits
            - Biological aspects of bone, cartilage and tendon regeneration 
            - Introduction: A Single Topic Issue on Mechanobiology
            - Transforming growth factors beta coordinate cartilage and tendon differentiation in the developing limb mesenchyme.
            - Influence of hydrostatic and distortional stress on chondroinduction 
Structure, function and adaptation of bone-tendon and bone-ligament complexes
Fibrocartilage in the extensor tendons of the human metacarpophalangeal joints.
            - Ultrastructure of fibrocartilages at the insertion of the rat Achilles tendon.

- Proteoglycans in Tendons:
            - Tendon proteoglycans: biochemistry and function
            - Aggrecan in bovine tendon.
            - Histochemistry defines a proteoglycan-rich layer in bovine flexor tendon subjected to bending.
            - Metabolism of proteoglycans in tendon
            - Structure and proteoglycan composition of specialized regions of the elastic tendon of the chicken wing
            - What happens when tendons bend and twist? Proteoglycans 
            - Metabolism of proteoglycans in tendon 
            - Proteoglycans and glycosaminoglycan fine structure in the mouse tail tendon fascicle
            - Characterisation of proteoglycans and their catabolic products in tendon and explant cultures of tendon
            - Hyaluronic acid in flexor tendon sheath fluid after sheath reconstructions in rabbits. A comparison between tendon sheath transplantation and conventional two stage procedures.
            - Abnormal collagen fibrils in tendons of biglycan/fibromodulin-deficient mice lead to gait impairment, ectopic ossification, and osteoarthritis 
            - Specific inhibition of type I and type II collagen fibrillogenesis by the small proteoglycan of tendon.

- Tendon Stem Cells:
            - Cell Orientation Affects Human Tendon Stem Cells Differentiation
            - Molecular targets for tendon neoformation
            - TENDON STEM CELLS
            - Tendons found to contain a small subset of previously unknown adult stem cells
            - Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche
            - Tendon stem cells found in a protein niche
            - Isolation and Characterization of Multipotent Rat Tendon-Derived Stem Cells.
            - Buffered platelet-rich plasma enhances mesenchymal stem cell proliferation and chondrogenic differentiation.
            - The regulation of tendon stem cell differentiation by the alignment of nanofibers
            - Hyaluronic Acid Modulates Cell Proliferation Unequally in Intrasynovial and Extrasynovial Rabbit Tendons In Vitro
            - Hydrostatic Pressure Enhances Chondrogenic Differentiation of Human Bone Marrow Stromal Cells in Osteochondrogenic Medium
            - Intrinsic differentiation potential of adolescent human tendon tissue: an in-vitro cell differentiation study
            - Mechanobiological conditioning of stem cells for cartilage tissue engineering

- Tendonopathy Models:
Changes in the composition of the extracellular matrix in patellar tendinopathy.
           - Chondrocyte Phenotype and Ectopic Ossification in Collagenase-induced Tendon Degeneration
           - In vitro model to study chondrogenic differentiation in tendinopathy.
           - Ossification of Achilles tendon - report of three cases 
           - The mechanism of formation of bony spurs (enthesophytes) in the Achilles tendon
           - Tendon Cell Behavior and Matrix Remodeling in Degenerative Tendinopathy
           - Expression of Bone Morphogenetic Protein-2 in the Chondrogenic and Ossifying Sites of Calcific Tendinopathy and Traumatic Tendon Injury Rat Models
           - In Vitro Model to Study Chondrogenic Differentiation in Tendinopathy
           - Fibrous cartilage in the rotator cuff: a pathogenetic mechanism of tendon tear?
           - Sustained expression of proteoglycans and collagen type III/type I ratio in a calcified tendinopathy model.
           - Chondrocyte Phenotype and Ectopic Ossification in Collagenase-induced Tendon Degeneration
           - Tendon Injury and Tendinopathy: Healing and Repair
           - Supraspinatus tendon composition remains altered long after tendon detachment
           - Endochondral ossification in Achilles and patella tendinopathy.

- Synovial Fluid:
           - The healing of freeze-dried rabbit flexor tendon in a synovial fluid environment.
           - The synovial cavity as a "tissue culture in situ"--science or nonsense?
           - Role of synovial fluid cells in the healing of flexor tendons.
           - Experimental studies on cellular mechanisms involved in healing of animal and human flexor tendon in synovial environment.
           - Experimental intrinsic healing of flexor tendons based upon synovial fluid nutrition.
           - Synovial fluid recruits human mesenchymal progenitors from subchondral spongious bone marrow

- ACL Reconstruction: Tendon Healing w/ Fibrocartilage Metaplasia in Bone Tunnels:

      What is fascinating about tendon to fibrocartilage metaplasia is that it may be an integral and necessary part of  healing for
bone to tendon healing in hamstring ACL reconstruction.  As noted by Wong, et al, "fibrocartilage transition zone in the direct
bone-tendon junction reduces stress concentration and protects the junction from failure."  In another report by Spalazzi et al,
the authors note that the "ACL integrates with subchondral bone through a fibrocartilage enthesis, which serves to minimize stress
concentrations and enables load transfer between two distinct tissue types."
Indeed, Soon, et al felt that tendon to bone healing in Achilles tendon allografts could be enhanced with the
addition of mesenchymal stem cells by specifically enhancing the formation of the fibrocartilaginous transition zone.
     - Articular cartilage increases transition zone regeneration in bone-tendon junction healing.
     - Mechanoactive scaffold induces tendon remodeling and expression of fibrocartilage markers.
     - An analysis of soft tissue allograft anterior cruciate ligament reconstruction in a rabbit model: a short-term study of the use of mesenchymal stem cells to enhance tendon osteointegration.

In the following diagram from (Rodeo), we see the microscopic edge of a hamstring tendon against
the side of a bone tunne.  We see a transition from tendon, to unmineralized fibrocartilage, to mineralized
fibrocartilage, to bone. 
           - The histology of tendon attachments to bone in man.

The collective findings of multiple basic science papers indicates that tendons have an intrinsic preprogrammed ability to manufacture elements
needed for fibrocartilage, and this fibrocartilage transition zone plays a complex and necessary role in tendon adaption and healing
with tendon reconstruction surgery.  This metaplastic process may be one of the most misunderstood and least appreciated biologic
processes in orthopaedics today.  My question is how far can we push this fibrocartilaginous metaplastic process inorder to heal
chondral injuries with tendon autografts.

- References:
            - Articular Cartilage Increases Transition Zone Regeneration in Bone-tendon Junction Healing 
            - Experimental replacement of the anterior cruciate ligament. A histological and microradiographic study.
            - Histological findings of tendon-bone healing following anterior cruciate ligament reconstruction with hamstring grafts
            - The biology of integration of the anterior cruciate ligament
            - Role of cell-cell interactions on the regeneration of soft tissue-to-bone interface.
            - Role of osteoblast-fibroblast interactions in the formation of the ligament-to-bone interface.
            - "Studies of Tendon-to-Bone Healing: Exploring Ways to Improve Graft Fixation Following Anterior Cruciate Ligament Reconstruction"
            - Mechanoactive Scaffold Induces Tendon Remodeling and Expression of Fibrocartilage Markers 
            - Long-term morphology of a healing bone–tendon interface: a histological observation in the sheep model
            - Tendon healing in a bone tunnel. Part II: Histologic analysis after biodegradable interference fit fixation in a model of anterior cruciate ligament reconstruction in sheep.
            - Healing Process of Bone-Patellar Tendon-Bone Graft in A Bone Tunnel: A Histological Study in Dogs.
            - An analysis of soft tissue allograft anterior cruciate ligament reconstruction in a rabbit model: a short-term study of the use of mesenchymal stem cells to enhance tendon osteointegration.
            - Graft healing in anterior cruciate ligament reconstruction.
            - Insertion of autologous tendon grafts to the bone: a histological and immunohistochemical study of hamstring and patellar tendon grafts.
            - Enhancement of tendon-bone integration of anterior cruciate ligament grafts with bone morphogenetic protein-2 gene transfer: a histological and biomechanical study.
            - Use of Bone Marrow Stromal Cells for Tendon Graft-to-Bone Healing. Histological and Immunohistochemical Studies in a Rabbit Model 
            - In  Vivo Evaluation of a Tri-Phasic Composite Scaffold for Anterior Cruciate Ligament-to-Bone Integration
            - Augmentation of Tendon–Bone Interface Healing With Low-intensity Pulsed Ultrasound
            - Enhancement of tendon graft osteointegration using mesenchymal stem cells in a rabbit model of anterior cruciate ligament reconstruction
             - Biology and augmentation of tendon-bone insertion repair

Rotator Cuff Repair:

Rotator cuff repair with periosteum for enhancing tendon–bone healing: a biomechanical and histological study in rabbits 

Original Text by Clifford R. Wheeless, III, MD.

Last updated by on Thursday, January 10, 2013 3:41 pm

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