Stem Cell Treatments to Repair Cartilage Defects in the Knee


Erosions of the cartilage that covers the surfaces at the ends of our leg bones has motivated several laboratories to undertake clinical studies to test new techniques to heal lost cartilage, particularly at the knee. Many of these techniques have their share of drawbacks and advantages, but the number of clinical trials to deal with cartilage lesions of the knee are increasing. Unfortunately, more work remains to be done, but much more is known about several of these techniques than before. This article will summarize many of these techniques.

Microfracture is a procedure in which several small holes are drilled into the end of the bone to enhance the migration of mesenchymal stem cells from the bone marrow to the site of the cartilage defect. These MSCs then differentiate into chondrocytes and make cartilage that fills the lesion with new cartilage. Unfortunately, the cartilage made in these cases is fibrocartilage and not hyaline cartilage. Fibrocartilage lacks the biomechanical strength and durability of hyaline cartilage and it typically deteriorates 18-24 months after surgery. When used to treat large lesions, 20-50% of all cases develop intralesional osteophytes and the sclerotic bone increases the failure rate of autologous chrondrocyte implantation 3-7X. Thus microfractionation is only performed under very specific conditions and only in young patients, since this technique does not work in older patients.

Microfracture

Autologous Chondrocyte Implantation or ACI uses a full-thickness punch biopsy from a low-weight-bearing region of the joint taken during an arthroscopic surgery. This biopsy contains chondrocytes that are grown in cell culture to a population of about 12-48 million chondrocytes, which are troweled into the lesion during a second arthroscopic surgery. Clinical trials have established that ACI is safe and effective for large knee lesions. Peterson and others and Minas and others have established that even after 10 years, patients who have been treated with ACI show good relief of pain and increased knee function.

In the Peterson study, questionnaires were sent to 341 patients. 224 of 341 patients replied to the questionnaires, and of these respondents, 74% of the patients reported their status as better or the same as the previous years 10-20 years after the procedure (mean, 12.8 years).  92% were satisfied and would have ACI again.  Knee function and pain levels were significantly better after the procedure than before.  From this study, Peterson and others concluded that ACI is an effective and durable solution for the treatment of large full-thickness cartilage and osteochondral lesions of the knee-joint, and that the clinical and functional outcomes remain high even 10 to 20 years after the implantation.

Minas and others analyzed data from 210 patients treated with ACI who were followed for more than 10 years. ACI provided durable outcomes with a survivorship of 71% at 10 years and improved function in 75% of patients with symptomatic cartilage defects of the knee at a minimum of 10 years after surgery. A history of prior marrow stimulation as well as the treatment of very large defects was associated with an increased risk of failure.
In comparison studies by Bentley and others, ACI produced superior results to mosaicplasty (osteochondral transplantation or cylinders of bone drilled form low-weight-bearing parts of the knee that are implanted in a mosaic fashion into the knee).  In the Bentley study, 10 of 58 ACI patients had failed grafts after 10 years, but 23 of 42 mosaicplasty patients had failed cartilage repair.  According to studies by Based and others, and Saris and others, ACI is also superior to microfractionation in the repair of large cartilage lesions (>3 cubic cm), but seems to provide the same outcomes as microfracture for smaller lesions, according to Knudsen and others.  There are drawbacks to ACI.  The tissue flap used to seal the cartilage implant sometimes becomes pathologically enlarged.  Other materials have been used to seal the patch, such as hyaluronic acid, or collagen types I and III, but the use of these materials increases the expense of the procedure and the likelihood that the immune system will response to the covering.  Also, ACI outcomes vary to such an extent that the procedure is simply too unstandardized at the present time to be used consistently in the clinic.

Autologous Cartilage Implantation

In an attempt to standardize ACI, several orthopedic surgeons have tried to add a supportive scaffold of some sort to the chondrocytes harvested from the patient’s body.  Several studies in tissue culture have shown that chondrocytes not only divide better, but also keep their identities as chondrocytes better in a three-dimensional matrix (see Grigolo et al, Biomaterials (2002) 23: 1187-1195 and Caron et al, Osteoarthritis Cartilage (2012) 20; 1170-1178).  Therefore, ACI has given way to MACI or Matrix-Induced Autologous Chondrocyte Implantation, which seeds the chondrocytes on an absorbable porcine-derived mixed collagen (type I and III) prior to implantation.  The implant is then secured into the debrided cartilage lesion by means of a fibrin cover.

Several case studies have shown that MACI has substantial promise, but individual case studies are the weakest evidence available.  To prove its superiority over ACI or microfracture surgery, MACI must be compared in controlled studies.  In the few studies that have been conducted, the superiority of MACI remains unproven to date.  Patients who received MACI or ACI showed similar clinical outcomes in two studies (Bartlett and others, Journal of Bone and Joint Surgery (2005) 87: 640-645; and Zeifang et al, American Journal of Sports Medicine (2010) 38: 924-933), although those who received MACI showed a significantly lower tendency for the graft to enlarge.  MACI is clearly superior to microfracture surgery (Basad, et al., Knee Surgery, Sports Traumatology and Arthroscopy (2010) 18: 519-527), but longer-term studies are needed to establish the superiority of MACI over other treatment options.

A slight variation of the MACI theme is to embed the chondrocytes in a gel-like material called hyaluronic acid (HA).  HA-embedded chondrocytes have been shown to promote the formation of hyaline cartilage in patients (Maracci et al., Clinical Orthopedics and Related Research (2005) 435: 96-105).  Even though the outcomes are superior for patients treated with HA-MACI, the recovery period is longer (Kon E, et al., American Journal of Sports Science (2011) 39: 2549-2567).  MACI is available in Europe but not the US to date.  FDA approval is supposedly pending.  Long-term follow-up studies are required to establish the efficacy of this procedure.

Future prospects for treating knee cartilage lesions include culturing collagen-seeded chondrocytes for a longer period of time than the three days normally used for MACI.  During these longer culture periods, the seeded chondrocytes mature, and make their own scaffolds, which ensure higher-quality cartilage and better chondrocyte engraftment (see Khan IM and others, European Cell Materials (2008) 16: 26-39).  Alternatively, joint cartilage responds to stress by undergoing cell proliferating and increasing in density.  This response is due to the production of growth factors such as Transforming Growth Factor-β1 and -β3 (TGF-β1 and TGF-β3).  This motivated some enterprising tissue engineers to use recombinant forms of these growth factors to grow cartilage in bioreactors under high-stress conditions.  Such a strategy has given rise to NeoCart, a tissue-engineered product that has gone through Phase I and II trials and has been shown in two-year follow-up studies to be safe and more effective than microfracture surgery (Crawford DC and others, Journal of Bone and Joint Surgery, American Volume. 2012 Jun 6;94(11):979-89 and Crawford DC, and others, Am J Sports Med. 2009 Jul;37(7):1334-43).

Mesenchymal stem cells (MSCs) from bone marrow and other sites have also been used to successfully treat cartilage lesions.  These types of treatments are less expensive than ACI and MACI, and do not require two surgeries as do ACI and MACI.  The studies that have been published using a patient’s own MSCs have been largely positive, although some pain associated with the site of the bone marrow aspiration is a minor side effect (see Centeno and others, Pain Physician (2008) 11:343-353; Emadedin, et al., Arch Iran Med (2012) 15: 422-428; Wong RL, et al., Arthroscopy (2013) 29: 2020-2028).  Fat-based MSCs have been tested as potential cartilage-healers in elderly patients (Koh YG, et al., Knee Surgery, Sports Traumatology, and Arthroscopy (Dec 2013, published on-line ahead of print date).  While these initial results look promising,, fat-based, MSCs have only just begun to be tested for their ability to regenerate cartilage.  Fat-based MSCs show different properties than their bone-marrow counterparts, and it is by no means guaranteed that fat-based MSCs can regenerate cartilage as well as MSCs from bone marrow.

Fresh cartilage grafts from donors (aka – cartilage allografts) use transplanted cartilage that has been freshly collected from a donor.  Fresh cartilage allografts have had positive benefits for young, active patients and the grafts have lasted 1-25 years (Gross AE, et al., Clinical Orthopedics and Related Research (2008) 466: 1863-1870).  Particulate cartilage allografts takes minced cartilage and lightly digests it with enzymes to liberate some of the cartilage-synthesizing chondrocytes, and then pats this material into the cartilage lesion, where it is secured with a fibrin glue plug.  The cartilage provides an excellent matrix for the synthesis of new cartilage, and the chondrocytes make new cartilage while seeded onto this cartilage scaffold.  Clinical experience with this technique includes a two-year follow-up in which MRI evidence showed good filling of the lesions (Bonner KF, Daner W, and Yao JQ, Journal of Knee Surgery 2010 23: 109-114 and Farr J, et al., Journal of Knee Surgery 2012 25: 23-29).  A variation on this technique uses a harvested hyaline cartilage plug that is glued into an absorbable scaffold before transplantation into the cartilage lesion.  This procedure had the same safety profile as microfracture surgery, but resulted in better clinical outcomes, high quality cartilage, and fewer adverse side effects (Cole JB et al., American Journal of Sports Medicine 2011 39: 1170-1179).  A clinical trial that tested this procedure remains uncompleted after the company suspended the trial because of conflicts with the FDA (Clinical Trial NCT00881023).

AMIC or Autologous Matrix-Induced Chondrogenesis is a cell-free treatment option in which the cartilage lesion is cleaned and filled subjected to microfracture, after which the lesion is filled with a mixed collagen matrix that is glued or stitched to the cartilage lesion.  The MSCs released by the microfracture procedure now move into a scaffold-laden cartilage lesion that induces the formation of hyaline cartilage.  This technique appears to aid the filling of full-thickness cartilage defects, and follow-up examinations have revealed that after 5 years, patients showed substantial improvements in knee function, pain relief and MRI analyses of knee cartilage showed high-quality cartilage in repaired lesion (Kusano T, et al., Knee Surgery, Sports Traumatology, and Arthroscopy 2012 20: 2109-2115; Gille J, et al., Archives of Orthopedic Trauma Surgery 2013 133: 87-93; Gille J, et al., Knee Surgery, Sports Traumatology, and Arthroscopy 2010 18: 1456-1464).

These are just a few of the new treatments of cartilage lesions of the knee and other joints.  As you can see, all of this will lead to greater repair of knee lesions and it is all being done without embryonic stem cells or destroying embryos.

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Published by

mburatov

Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).