Autologous matrix-induced chondrogenesis
Encyclopedia
Autologous Matrix-Induced Chondrogenesis (AMIC) is a biological treatment option which repairs articular cartilage damage
. It combines microfracture surgery
with the application of a bi-layer collagen I/III membrane.
AMIC achieves pain relief and restores functionality in the joint with the goal to regain full mobility, allowing going back to previous lifestyle and activity level. It slows down cartilage
degeneration with the intent to avoid or delay partial or total joint replacement
(e.g. knee replacement
) surgery.
AMIC is based on microfracturing which relies on the body’s own healing potential. Blood
and bone marrow
which are released through tiny holes in the subchondral bone plate, fill the damaged cartilage area with a so called super-clot. This blood clot contains all the elements (e.g. progenitor cell
s, mesenchymal stem cells (MSCs)
, cytokine
s and growth factor
s) necessary to form new cartilage repair tissue as response to the encountered injury.
Adding a collagen membrane to the forming super clot secures it and improves overall clot stability. It also enhances the primary defect fill which is an important parameter for good outcome. Furthermore the application of a collagen membrane provides an environment where cells can adhere, proliferate and produce repair tissue in a protected setting. The originally proposed collagen membrane for AMIC (Chondro-Gide, Geistlich Pharma AG, Switzerland) consists of two sides, two layers (bi-layer design), one dense, compact side and a loose side.
Its clinical efficiency in autologous chondrocyte implantation (ACI)
, another cartilage repair technique for larger cartilage lesions, has been studied extensively.
AMIC surgery is currently performed to treat cartilage damage in the knee
and in the ankle (talus
).
of the cartilage damage and decision for an AMIC procedure a mini arthrotomy
is performed.
First the cartilage defect is exposed and cleaned whereby all unstable degenerated cartilage, including the calcified cartilage layer, are carefully removed. An imprint of the defect is then taken using a sterile
moldable material (e.g. aluminium foil
) and transferred to the collagen membrane which is cut to shape. The surgeon then creates tiny holes/fractures in the subchondral bone plate (microfracturing
) with a special awl. Blood
and bone marrow
(containing stem cell
s) are released forming a blood clot
which contains cartilage forming elements. The correctly sized collagen membrane is added to the microfractured area either by fibrin glue
(autologous or commercially available) or suturing. Through flexion of the joint, the stable positioning of the membrane is verified and the wound is closed.
A critical phase and actually essential requirement for satisfying outcome of the AMIC surgery is the compliance to a strict physical therapy
program. Guidelines and recommendations exist, though they have to be adapted to the individual patients needs.
Microfracture surgery was developed by Dr. Steadman in the late 80’s and early 90’s. It is a well documented cartilage repair technique and first line treatment option for small cartilage lesions. AMIC evolved with the aim to improve some of the shortfalls of microfracture surgery as for instance variable repair cartilage volume and functional deterioration over time. Additionally it was intended to provide a simple technique for securely retaining the fragile blood clot in larger defects and to possibly enhance the chondrogenesis of MSCs.
The first in-vitro work demonstrating that a collagen membrane can retain cartilage building cells (e.g. MSCs
) from bone marrow was published in 2006 by Kramer et al.. After perforation of the subchondral bone (microfracturing) the collagen membrane was added to the forming super-clot. Then MSCs were recovered from a tiny surplus of bone marrow soaked membrane. As a proof of their existence, MCSs were successfully differentiated
into the adipogenic
, osteogenic and most importantly chondrogenic
lineage. Chondrification (also known as chondrogenesis
) is the underlying process of cartilage formation from condensed mesenchyme
tissue, which differentiates into chondrocytes and begins secreting the molecules that form the extracellular matrix
, the cartilage repair tissue.
In another in-vitro study Dickhut et al. investigated whether a combination of a collagen membrane (Chondro-Gide) with fibrin glue supports in-vitro chondrogenesis of MSCs and allowed for local release of bioactive transforming growth factor beta-1 (TGF-β1)
. They could show, that the combination provided high biofunctionality with improved chondrogenesis and long term local supply of TGF-β1. TGF-β1 is a secreted protein that performs many cellular functions, including the control of cell growth, cell proliferation, cell differentiation
and apoptosis
. Additionally Dickhut et al. could demonstrate that the form stability of the forming repair tissue was enhanced when compared to collagen-membrane-free constructs.
The addition of a collagen membrane to microfractured cartilage lesions has also been tested in a sheep study by Gille et al.. It could be confirmed that the thickness of the repair tissue was greater when a scaffold, especially a collagen I/III membrane, was used as compared to microfracture alone. Hence the authors concluded that repair tissue formation was promoted.
The same author reported first clinical results with the AMIC technique in 2010. A total of 27 patients who underwent AMIC surgery between 2003 and 2005 were included in this prospective investigation. The follow-up period was between 24 and 62 months with a mean of 37 months. The mean age of the patients was 39 years (range 16 – 50 years). The mean defect size was 4.2 cm2 (range 1.3 - 8.8 cm2). Three patients had to be excluded from the study. 20 of the 23 patients questioned answered that they were highly satisfied with the results after surgery and stated overall improvement of knee function. The outcome scores applied (Lysholm, ICRS, Meyer, Tegner, Cincinatti) showed significant increase up to 24 months with a slight decrease from three years post surgery. Patients with lesions larger 8 cm2 had greatly reduced scores. Gille et al. concluded that treatment of chondral knee lesions with the AMIC technique is effective and safe in appropriately selected cases.
Further clinical description of the AMIC technique and it’s early results can be found in the papers by Benthien, de Girolamo and Wiewiorski.
Articular cartilage damage
Cartilage structures and functions can be damaged. Such damage can result from a variety of causes, such as a bad fall or traumatic sport-accident, previous knee injuries or wear and tear over time...
. It combines microfracture surgery
Microfracture surgery
Microfracture surgery is one of the articular cartilage repair surgical techniques that works by creating tiny fractures in the underlying bone. This causes new cartilage to develop from a so-called super-clot...
with the application of a bi-layer collagen I/III membrane.
AMIC achieves pain relief and restores functionality in the joint with the goal to regain full mobility, allowing going back to previous lifestyle and activity level. It slows down cartilage
Cartilage
Cartilage is a flexible connective tissue found in many areas in the bodies of humans and other animals, including the joints between bones, the rib cage, the ear, the nose, the elbow, the knee, the ankle, the bronchial tubes and the intervertebral discs...
degeneration with the intent to avoid or delay partial or total joint replacement
Joint replacement
Replacement arthroplasty [from Greek arthron, joint, limb, articulate, + -plassein, to form, mould, forge, feign, make an image of], or joint replacement surgery, is a procedure of orthopedic surgery in which the arthritic or dysfunctional joint surface is replaced with an orthopaedic prosthesis...
(e.g. knee replacement
Knee replacement
Knee replacement, or knee arthroplasty, is a surgical procedure to replace the weight-bearing surfaces of the knee joint to relieve the pain and disability of osteoarthritis. It may be performed for other knee diseases such as rheumatoid arthritis and psoriatic arthritis...
) surgery.
Background
The AMIC procedure was first proposed by Behrens in 2003. It aims to extend the use of microfracture surgery to larger cartilage lesions > 2.5 cm2.AMIC is based on microfracturing which relies on the body’s own healing potential. Blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
and bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
which are released through tiny holes in the subchondral bone plate, fill the damaged cartilage area with a so called super-clot. This blood clot contains all the elements (e.g. progenitor cell
Progenitor cell
A progenitor cell is a biological cell that, like a stem cell, has a tendency to differentiate into a specific type of cell, but is already more specific than a stem cell and is pushed to differentiate into its "target" cell...
s, mesenchymal stem cells (MSCs)
Mesenchymal stem cell
Mesenchymal stem cells, or MSCs, are multipotent stem cells that can differentiate into a variety of cell types, including: osteoblasts , chondrocytes and adipocytes...
, cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s and growth factor
Growth factor
A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes....
s) necessary to form new cartilage repair tissue as response to the encountered injury.
Adding a collagen membrane to the forming super clot secures it and improves overall clot stability. It also enhances the primary defect fill which is an important parameter for good outcome. Furthermore the application of a collagen membrane provides an environment where cells can adhere, proliferate and produce repair tissue in a protected setting. The originally proposed collagen membrane for AMIC (Chondro-Gide, Geistlich Pharma AG, Switzerland) consists of two sides, two layers (bi-layer design), one dense, compact side and a loose side.
Its clinical efficiency in autologous chondrocyte implantation (ACI)
Autologous chondrocyte implantation
Autologous chondrocyte implantation is a biomedical treatment that repairs damages in articular cartilage. ACI provides pain relief while at the same time slowing down the progression or considerably delaying partial or total joint replacement surgery...
, another cartilage repair technique for larger cartilage lesions, has been studied extensively.
AMIC surgery is currently performed to treat cartilage damage in the knee
Knee
The knee joint joins the thigh with the leg and consists of two articulations: one between the fibula and tibia, and one between the femur and patella. It is the largest joint in the human body and is very complicated. The knee is a mobile trocho-ginglymus , which permits flexion and extension as...
and in the ankle (talus
Talus bone
-External links:* *...
).
Procedure
Autologous Matrix Induced Chondrogenesis (AMIC) surgery is a single step procedure. After arthroscopic evaluationArthroscopy
Arthroscopy is a minimally invasive surgical procedure in which an examination and sometimes treatment of damage of the interior of a joint is performed using an arthroscope, a type of endoscope that is inserted into the joint through a small incision...
of the cartilage damage and decision for an AMIC procedure a mini arthrotomy
Arthrotomy
An Arthrotomy is a process involving creating an opening in a joint.It may be involved in drainage.-References:...
is performed.
First the cartilage defect is exposed and cleaned whereby all unstable degenerated cartilage, including the calcified cartilage layer, are carefully removed. An imprint of the defect is then taken using a sterile
Sterilization (microbiology)
Sterilization is a term referring to any process that eliminates or kills all forms of microbial life, including transmissible agents present on a surface, contained in a fluid, in medication, or in a compound such as biological culture media...
moldable material (e.g. aluminium foil
Aluminium foil
Aluminium foil is aluminium prepared in thin metal leaves, with a thickness less than , thinner gauges down to are also commonly used. In the USA, foils are commonly gauged in mils. Standard household foil is typically thick and heavy duty household foil is typically .The foil is pliable, and...
) and transferred to the collagen membrane which is cut to shape. The surgeon then creates tiny holes/fractures in the subchondral bone plate (microfracturing
Microfracture surgery
Microfracture surgery is one of the articular cartilage repair surgical techniques that works by creating tiny fractures in the underlying bone. This causes new cartilage to develop from a so-called super-clot...
) with a special awl. Blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
and bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
(containing stem cell
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...
s) are released forming a blood clot
Thrombus
A thrombus , or blood clot, is the final product of the blood coagulation step in hemostasis. It is achieved via the aggregation of platelets that form a platelet plug, and the activation of the humoral coagulation system...
which contains cartilage forming elements. The correctly sized collagen membrane is added to the microfractured area either by fibrin glue
Fibrin glue
Fibrin glue is a formulation used to create a fibrin clot. It is made up of fibrinogen and thrombin that are injected through one head into the site of a fibrin tear. Thrombin is an enzyme and converts the fibrinogen into fibrin between 10 and 60 seconds and acts as a tissue adhesive. It may also...
(autologous or commercially available) or suturing. Through flexion of the joint, the stable positioning of the membrane is verified and the wound is closed.
A critical phase and actually essential requirement for satisfying outcome of the AMIC surgery is the compliance to a strict physical therapy
Physical therapy
Physical therapy , often abbreviated PT, is a health care profession. Physical therapy is concerned with identifying and maximizing quality of life and movement potential within the spheres of promotion, prevention, diagnosis, treatment/intervention,and rehabilitation...
program. Guidelines and recommendations exist, though they have to be adapted to the individual patients needs.
Clinical Results
In general various factors have been identified known to influence the clinical result after cartilage repair regardless of the technique used. Amongst them are the species and age of the individual, the size and localization of the articular cartilage defect, the surgical technique, and the postoperative rehabilitation protocol. The latter has been found especially important for microfracture surgery and therefore for AMIC.Microfracture surgery was developed by Dr. Steadman in the late 80’s and early 90’s. It is a well documented cartilage repair technique and first line treatment option for small cartilage lesions. AMIC evolved with the aim to improve some of the shortfalls of microfracture surgery as for instance variable repair cartilage volume and functional deterioration over time. Additionally it was intended to provide a simple technique for securely retaining the fragile blood clot in larger defects and to possibly enhance the chondrogenesis of MSCs.
The first in-vitro work demonstrating that a collagen membrane can retain cartilage building cells (e.g. MSCs
Mesenchymal stem cell
Mesenchymal stem cells, or MSCs, are multipotent stem cells that can differentiate into a variety of cell types, including: osteoblasts , chondrocytes and adipocytes...
) from bone marrow was published in 2006 by Kramer et al.. After perforation of the subchondral bone (microfracturing) the collagen membrane was added to the forming super-clot. Then MSCs were recovered from a tiny surplus of bone marrow soaked membrane. As a proof of their existence, MCSs were successfully differentiated
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
into the adipogenic
Adipogenesis
Adipogenesis is the process of cell differentiation by which preadipocytes become adipocytes.. Adipogenesishas been one of the most intensively studied model of cellular differentiation.-References:...
, osteogenic and most importantly chondrogenic
Chondrogenesis
-Cartilage in fetal development:In embryogenesis, the skeletal system is derived from the mesoderm germ layer. Chondrification is the process by which cartilage is formed from condensed mesenchyme tissue, which differentiates into chondrocytes and begins secreting the molecules that form the...
lineage. Chondrification (also known as chondrogenesis
Chondrogenesis
-Cartilage in fetal development:In embryogenesis, the skeletal system is derived from the mesoderm germ layer. Chondrification is the process by which cartilage is formed from condensed mesenchyme tissue, which differentiates into chondrocytes and begins secreting the molecules that form the...
) is the underlying process of cartilage formation from condensed mesenchyme
Mesenchyme
Mesenchyme, or mesenchymal connective tissue, is a type of undifferentiated loose connective tissue that is derived mostly from mesoderm, although some are derived from other germ layers; e.g. some mesenchyme is derived from neural crest cells and thus originates from the ectoderm...
tissue, which differentiates into chondrocytes and begins secreting the molecules that form the extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
, the cartilage repair tissue.
In another in-vitro study Dickhut et al. investigated whether a combination of a collagen membrane (Chondro-Gide) with fibrin glue supports in-vitro chondrogenesis of MSCs and allowed for local release of bioactive transforming growth factor beta-1 (TGF-β1)
TGF beta 1
Transforming growth factor beta 1 or TGF-β1 is a polypeptide member of the transforming growth factor beta superfamily of cytokines. It is a secreted protein that performs many cellular functions, including the control of cell growth, cell proliferation, cell differentiation and apoptosis...
. They could show, that the combination provided high biofunctionality with improved chondrogenesis and long term local supply of TGF-β1. TGF-β1 is a secreted protein that performs many cellular functions, including the control of cell growth, cell proliferation, cell differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
and apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. Additionally Dickhut et al. could demonstrate that the form stability of the forming repair tissue was enhanced when compared to collagen-membrane-free constructs.
The addition of a collagen membrane to microfractured cartilage lesions has also been tested in a sheep study by Gille et al.. It could be confirmed that the thickness of the repair tissue was greater when a scaffold, especially a collagen I/III membrane, was used as compared to microfracture alone. Hence the authors concluded that repair tissue formation was promoted.
The same author reported first clinical results with the AMIC technique in 2010. A total of 27 patients who underwent AMIC surgery between 2003 and 2005 were included in this prospective investigation. The follow-up period was between 24 and 62 months with a mean of 37 months. The mean age of the patients was 39 years (range 16 – 50 years). The mean defect size was 4.2 cm2 (range 1.3 - 8.8 cm2). Three patients had to be excluded from the study. 20 of the 23 patients questioned answered that they were highly satisfied with the results after surgery and stated overall improvement of knee function. The outcome scores applied (Lysholm, ICRS, Meyer, Tegner, Cincinatti) showed significant increase up to 24 months with a slight decrease from three years post surgery. Patients with lesions larger 8 cm2 had greatly reduced scores. Gille et al. concluded that treatment of chondral knee lesions with the AMIC technique is effective and safe in appropriately selected cases.
Further clinical description of the AMIC technique and it’s early results can be found in the papers by Benthien, de Girolamo and Wiewiorski.
See also
- CartilageCartilageCartilage is a flexible connective tissue found in many areas in the bodies of humans and other animals, including the joints between bones, the rib cage, the ear, the nose, the elbow, the knee, the ankle, the bronchial tubes and the intervertebral discs...
- MicrofracturingMicrofracture surgeryMicrofracture surgery is one of the articular cartilage repair surgical techniques that works by creating tiny fractures in the underlying bone. This causes new cartilage to develop from a so-called super-clot...
- Knee osteoarthritisKnee osteoarthritisKnee osteoarthritis is a degenerative disease of the knee joint. It is more common in people older than 40 years. Women have greater chance to be affected.-Signs and symptoms:Some of the signs and symptoms associated with knee osteoarthritis include:* Pain...
- Knee painKnee painKnee pain is a common complaint for many people. There are several factors that can cause knee pain. Awareness and knowledge of knee pain causes lead to faster diagnosis and treatment. Knee pain can be related to knee joint or around the knee.-Knee joint:...