We are busy trying to develop Cartilage replacement technologies to prevent the knee from wearing out and needing artificial replacement. This article gives you the current update on what the future looks like for state-of-the-art knee surgery. Tissue Engineering is advancing...
DeNovo NT cartilage transplantation has arrived. Read more detail.
Orthobiologics and Biosurgery
Some of other recent innovations in knee surgery:
Some of the up and coming ‘in the works’ innovations- in clinical trials
DeNovu ET (Engineered Tissue) (Zimmer Inc)
Here’s a cool PowerPoint presentation about Hyalograft C:
a couple companies that are making it:
Here’s a BioMed Central paper on MSC: http://www.biomedcentral.com/
Here’s a paper about Cartistem™: http://www.globalbiotechforum.
Biologics: Alternatives to Arthroplasty
CELL-BASED TECHNIQUES UTILIZING CHONDROCYTES
The majority of chondrocyte-based techniques are based on the autologous chondrocyte implantation (ACI)
tcchnique. They attempt to improve upon the perceived shortcomings of ACI. Including the need for a periosteal patch, suture fixation, uneven cell distribution within the defect, potential cell leakage from the defect, and the need for prior cartilage harvest. This is achieved by the use of biocompatible membranes, advanced fixation devices, such as staples and glues, matrix-bound chondrocytes rather than cell suspensions, allogenic tissue, and special harvesting devices.
BioCart II
BioCart II (ProChon Biotech Ltd, Rehovot, Israel) utilizes arthroscopically harvested and ex-vivo cultured autologous chondrocytes. Autologous serum, enhanced with a proprietary growth factor, is used during the cell culture process. A scaffold is prepared from fibrin and recombinant hyaluronic acid to provide a three-dimensional (3-D) open pore structure onto which the expanded cells are transferred 3 to 4 days before implantation; the resultant matrix is fibrin glued into the prepared defect through a mini-arthrotomy. The company plans to incorporate bioengineered proteins or peptides such as gtowth fuetors into the scaffold to accelerate cell propagation and cartilage formation in future developments. Large animal testing of BioCart II demonstrated the formation of new articular cartilage with good integration into the host tissue and improved histologic appearance when compared with microfracture.
CARTILAGE AUTOGRAFT IMPLANTATION SYSTEM
The Cartilage Autograft Implantation System (CAIS, Depuy-Mitek, Raynham, MA) is a single-stage procedure utilizing autologous morcellized cartilage glued onto a synthetic, bioabsorbable scaffold. The procedure begins with an arthroscopic cartilage biopsy harvested with a special device that morcellizes the biopsy material into 1-2 mm pieces, which are then uniformly dispersed onto a scaffold where they are secured with fibrin glue. After the arthroscopic harvest, the defect is further assessed through a mini-arthrotomy and prepared in a standard fashion to create stable perpendicular shoulders and a base devoid of
the calcified layer. The scaffold with attached morcellized cartilage is cut to fit the defect and secured in place (cartilage pieces facing bone) with absorbable staples. Preclinical animal studies have demonstrated the ability of chondrocytes to migrate out of the morcellized cartilage, multilply, and produce new hyaline matrix. The company is currently planning for a pivotal trial after the recent completion of an international pilot program with separate clinical studies in Europe and the United States.
Cartilage Repair System
The Cartilage Repair System (CaReS, Arthro Kinetics Inc, Boston, MA) is a second-generation ACI technology currently approved in Europe for the treatment of cartilage defects of 2 to 10 cm2 in size. Since European approval was granted in October 2002, more than 1000 patients have been treated with this technique. It is based on a 3D cell culture in a Type I collagen matrix (derived from rat tail tendon). After arthroscopic biopsy, the cartilage specimen is shipped to the culturing facility in autologous blood. The cell-seeded matrix is ready for implantation after approximately 2 weeks and is implanted through a mini-arthrotomy utilizing glue fixation. The company is planning to reduce the culturing process to 1 week to expedite time to implantation. There are plans to start US clinical trials in the foreseeable future.
CARTIPATCH
Cartipatch (Tissue Bank of France, Mions, Frauce) combines arthroscopically harvested autologous chondrocytes with a 3D hydrogel scaffold of agarose and alginate that is derived from medical-grade algae. The resultant circular patches of 10, 14, or18 mm diameter are implanted through a miniarthrotomy; multiple patches can be combined to cover larger lesions. The chandral defect is first debrided and then reamed to a depth of 4 mm, followed by insertion of the patch, which adheres to the bed without use of additional glue or sutoring. A prospective multicenter trial was recently concluded in Europe, which demonstrated significant improvements in functional scores, magnetic resonance imaging (MRI) appearance, and histology in 17 patients. Cartipatch is indicated for traumatic chondral and osteochondritis dissecans lesions of 1 to 8 cm2. It is currently not available in the United States.
CHONDROCELECT
ChondroCelect (Tigenix, Leuven, Belgium) is an ACI technique that utilizes a unique genetic monitoring system to optimize the cell culturing process and evaluate the chondrocyte quality. Researchers at the company have identifted several gene markers that can predict the quality of the resultant repair tissue after cell implantation and have optimized their culturing process to maintain expression of these markers. A cartilage biopsy is harvested arthroscopically and sent to the culturing facility for cell culture. The cells are scored, and biopsies that demonstrate poor expression of these markers (less than 5% of samples) are withheld from implantation. Chondrocytes are implanted as a suspension under a periosteal or collagen cover as with first-generation ACl; a second-generation implant is currently under development in conjunction with Fidia (AbanaTerme, Italy) in which cells are seeded onto a hyaluronic acid scaffold and implanted with glue fixation or limited suturing. ChondroCelect recently completed a large randomized controlled trial against microfracture in Europe, which demonstrated improved histology and comparable short·term clinical outcomes. Future plans include a US trial with the second-generation construct.
DeNovo NT
DeNovo NT (Natural Tissue) (Zimmer Inc, Warsaw, IN/ISTO Technologies Inc, St. Louis, MO) is an allograft process using juvenile donor cartilage, which is minced into small pieces without employing enzymatic or chemical treatments. The cartilage pieces are implanted into the cartilage defect using fibrin adhesive for fixation. Because the tissue is "minimally manipulated," it is regulated as an allograft tissue rather than a biological implant. This is similar to oversight for many other allograft products such as meniscus allograft. Therefore, it is not regulated by the FDA. Standard-of-care applications are being performed in selected centers and a prospective outcomes study is currently being conducted.
DENovoET
DeNovu ET (Engineered Tissue) (Zimmer Inc) is related to the DeNovo NT graft, both being allogenic tissue from human juvenile donor joints. It differs in that the cells are isolated and expanded in vitro similar to standard ACI techniques. The expanded cells are cryopreserved in a cell bank from which a huge number of grafts can be grown. Before implantation, the cells are thawed and cultured in a serum- and scaffold-free process to produce a hyaline-like cartilage graft, which is implanted with fibrin adhesive. A US pilot study recently completed enrollment.
MATRIX-INDUCED AUTOLOGOUS CHONDROCYTE IMPLANTATION
Matrix-induced autologous chondrocyte implantation (MACI) (Genzyme Europe, Naarden, Netherlands) was one of the first "second-generation" products in Europe and was rapidly accepted, often in place of conventional ACI. MACI also requires an initial arthroscopy to obtain autologous chondrocytes, which are expanded in a two-dimensional (2-D) cell culture for 2 to 4 weeks. Prior to shipment, the cells are seeded and grown on a porcine-derived type I/III collagen bilayer matrix for several additional days. This matrix is cut to match the defect and is implanted either through an arthrotomy or arthroscopically with fibrin glue fixation and, rarely, limited suturing. The avoidance of a periosteal patch decreases surgical time and reoperation rate due to patch hypertrophy (less than 5% in some studies).
European trials have shown clinical results equal to the first-generation ACI technique with a reduction in patch-related reoperation rate from more than 30% to less than 5%. Established in Europe, MACI is currently not available in the US as it is not currently approved by the FDA. US clinical trials are being considered, but no official dates have been announced. An additional European investigation is currently in progress.
NeoCart
NeoCart (Histogenics, Waltham MA) is a two-stage procedure using arthroscopically harvested autologous
chondrocytes that are seeded onto a 3D collagen honeycomb matrix with the goal to improve stratification. The carrier matrix is cultured in a hydrostatic reactor under pressure in a low O2 environment that encourages S-GAG production and a type II/type I collagen ratio similar to hyaline cartilage. The matrix is implanted with use of a proprietary adhesive with superior mechanical strength than fibrin glue. Preclinical studies have demonstrated integration of the matrix with the subchondral bone and surrounding cartilage. A phase I/II study recently completed enrollment and demonstrated both clinical improvement and good fill on MRI, while a randomized controlled trial is currently enrolling subjects.
CELL-BASED TECHNIQUES UTILIZING STEM CELLS
One goal in cartilage repair is the ability to perform single-step surgery. In addition to the above-mentioned allogenic cell products, mesenchymal stem cells represent another potential technique to avoid the need to harvest autologous chondrocytes in a separate procedure. The bone marrow and other tissues such as peripheral blood and subcutaneous fat have been described as a useful source of cells for the restoration of damaged tissue. Mesenchymal stem cells (MSC) have a high proliferation rate and a multilineage differentiation potential into hematopoietic stem cells, adipogenic, osteogenic, and chondrogenic cells, resulting in the formation of blood, fat, bone, and cartilage, respectively.
Stem cells have become a focus of tissue engineering and are being investigated for applications ranging from the organ (bladder transplants) to the tissue (cartilage, muscle) level. Investigators hope to create tissue banks from stem cells that can be ordered for patients with cartilage defects; alternatively, stem cells can be obtained from the patient during a prior office visit (peripheral blood) or intraoperatively through a bone marrow aspiration. The cells are then combined with a carrier substance and placed into the lesion, potentially differentiating into chondrocytes that produce a reparative tissue.
ALLOGENIC MESENCHYMAL UMBILICAL CORD BLOOD STEM CELLS
This stem cell-based technique from Medipost (South Korea) utilizes allogenic mesenchymal stem cells derived from umbilical cord blood. The stem cells are extracted from placental blood after delivery, concentrated, and placed in cell culture. For implantation, a batch of cells is removed from culture and mixed with hyaluronic acid to form a carrier gel that is placed into the defect through a mini-arthrotomy. Preclinical animal studies have demonstrated the production of a repair tissue rich in type II collagen with good integration to the subchondral bone and the adjacent cartilage, A phase I clinical trial was recently concluded in South Korea, and additional human trials are planned abroad and in the United States for the near future.
CHONDROGEN
Chondrogen (Osiris Therapeutics, Baltimore, MD) is a preparation of adult allogenic mesenchymal stem cells specifically formulated for direct injection into the knee joint. The mesenchymal stem cells in Chondrogen are obtained from the bone marrow of healthy adult donors and are expanded in culture to produce many treatments from a single donation. Preclinical animal studies using Chondrogen demonstrated chondral protection in a postmenisectomy animal arthritis model, in which the meniscus showed signs of regeneration. A double-blind, controlled Phase I/II clinical trial evaluated a single injection
of Chondrogen in patients who had undergone a partial menisectomy. This recently completed study showed clinical improvement in the Chondrogen group compared to controls, but no significant increase in meniscal volume after meniscectomy, one of the study endpoints. The chondroprotective effect will be further evaluated in an additional long-term clinical study.
PLATELET-RICH PLASMA AND AUTOLOGOUS MESENCHYMAL STEM CELLS
This technique, developed by Dr. Alberto Gobin (Milan, Italy), is currently being investigated in Europe and utilizes a combination of autologous mesenchymal stem cells and platelet-rich plasma (PRP). In the operating room, 40 to 60 mL of bone marrow is aspirated from the iliac crest and concentrated 4- to 6-fold using a centrifuge (Marrowstim, Biomet).
Also, 30 to 60 mL of peripheral blood is taken from the patient to prepare PRP, the plasma is separated from the red blood cells by centrifugation (Harvest Smart PreP2 System, Harvest Technologies, Plymouth, MA), followed by a second centrifugation step to concentrate the platelets for optimal plasma volume and platelet number. The bone marrow concentrate (BMC) is mixed with PRP and activated with autologous or allogenic thrombin to produce a sticky clot material that is pasted into the defect and covered with a collagen membrane. An early clinical study involving 20 patients followed for 2 years has demonstrated encouraging results; additional trials are pending.
CELL-FREE TECHNIQUES
The majority of cell-based techniques involve an ex vivo culturing process. These processes significantly increase the cost and several but not all, of the culturing methods create concern regarding cell de-differentiation into a more fibroblastic type. Cell-free implants attempt to affect defect repair by harnessing and modulating inherent reparative responses by implantation of scaffolds and/or growth factors. These techniques have the potential for single-stage, off-the-shelf implantation.
AUTOLOGOUS MATRIX-INDUCED CHONDROGENESIS
Autologous Matrix-Induced Chondrogenesis (AMIC) (Geistlich Pharma AG, Wolhusen, Switzerland) is a new procedure combining two established techniques – microfracture and collagen membranes – to potentially improve the quality of the reparative tissue after marrow stimulation. After conventional microfracture has been performed, a type I/III bilayer collagen membrane, such as the one used in the MACI technique, is secured over the defect to cover the clot and marrow elements. It has been theorized that a mechanically more stable repair tissue will be of higher quality and durability. This technique is currently being investigated in Europe, and small clinical studies with limited follow-up have demonstrated promising results.
GELRIN
Gelrin (Regentis Biomaterials Ltd, Or Akiva, Israel) is a polyethylene glycol (PEG) polymer hydrogel that is cross-linked with less than 1% fibrinogen chains. It provides a biodegradable scaffold that can assist local cells involved in tissue repair. The implant degradation by proteases can be modified for specific applications and the material can be photopolymerized into a hydrogel in-situ, allowing for minimally invasive delivery. The matrix can also be modified as a delivery vehicle for inductive growth factors. Preclinical animal studies demonstrated hyaline-like cartilage regeneration, and human trials are currently being considered.
TRUFIT PLUG
The TruFit plug (Smith & Nephew, Andover, MA) consists of polyactide-co-glycolide, calcium sulfate and polyglycolide fibers and was originally designed and FDA approved as a bone-void filler (eg, after autologous osteochondral grafting). The plugs have been used for primary cartilage repair in Europe, but are not FDA approved for this indication in the United States. The material can provide a scaffold for bone marrow elements and is thought to aid in the reparative response. The company is currently considering a clinical trial designed to evaluate a potential cartilage repair indication; however, no formal trials have been conducted to date.
What the article above does NOT go on to say is that your access to these innovations is not guaranteed. Consider these important points.
As you can see, there are a lot of competing forces. Performing these biosurgical procedures takes specialized training that many orthopaedic surgeons don’t have, while at the same time, advances in technology are making biological solutions more available. Unfortunately, increasing costs of research and development, and increasing utilization make these solutions unattractive to your insurance company. The insurance companies plan to pass on their costs to you, the hospitals and the doctors…and in the end, the patients may not have the access they need to take advantage of these innovations – and fix problems before they become more catastrophic.
Cartilage Repair Center. Org MRI of Articular Cartilage
MRI of Articular Cartilage. Medscape
Aug 17, 2009 Pioneering Cartilage Restoration Surgery - DeNovo NT:
Early in 2009, the 1st DeNovo natural tissue graft cartilage transplant in the Southeastern United States was performed by Jon Hyman, MD, at Emory-Adventist Hospital
Jul 18, 2009 Carlos Delago, Alex Rodriguez and Kurt Warner: hip surgery: Alex Rodriguez had arthroscopic hip surgery 3/9/09 and now Kurt Warner 3/18/09. Carlos Delgado has his hip scoped 5/19/09. The list just grows, and grows...
Jun 30, 2009 More Athletes Getting Hip Arthroscopy: in 2009,more professional athletes have been undergoing arthroscopic hip surgery, Alex Rodriquez, Chase Utley, Kurt Warner...
Oct 8, 2008 New Cartilage Restoring Surgery trying to enter US Markets:
DeNovo ET, a scaffold-free, living cartilage implant, offers a one-step alternative to current cartilage repair.
A Phase I/II clinical trial for DeNovo ET is underway at three sites in the United States
Sep 2, 2009 Newest Advances in Knee BioSurgery: We are busy trying to develop cartilage restoration technologies to prevent the knee from wearing out and needing prosthetic metal replacement. This article gives you the current update on what the future looks like for state-of-the-art knee surgery.
Aug 1, 2009 Ways to Preserve Your Joints: Here we present the latest 2009 perspectives on staying healthy and preserving your joints.
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