Cartilage is a very unique tissue type as it does not contain blood vessels or nerves and therefore has a very limited capacity for regeneration.
In addition, aging populations, increased prevalence in obesity, and more young people enjoying active sports contribute to an increase in osteoarthritis patients.
The current treatment options for damaged knee cartilage include drug treatment for the alleviation of pain, a bone marrow stimulation treatment (also known as micro-fracture), total or partial knee replacements, ACI and artificial knee replacement surgeries, each of these are explained in more detail below.
Micro-fracture: Knee micro-fracture surgery is a common procedure used to repair damaged knee cartilage and is usually suitable for patients that have articular cartilage damage of such depth and severity that it has eroded the cartilage to the bone. The procedure for a micro-fracture is for a surgeon to clear the injured (cartilage defect) area of the knee using arthroscopic tools. Small holes are drilled into the bone. The idea behind this intentional injury to the bones is to stimulate the body (by causing bone-marrow bleeding) to respond to the injury. When small holes are drilled into the bone, this prompts the body to respond by repairing the injured site by increasing blood flow to the injury site and allowing more blood vessels and bone marrow cells to come into contact with the injury. The cells released from the bone marrow may eventually prompt the growth of new cartilage.
Several drawbacks of micro-fracture surgery exist, including size of the cartilage defect and age of the patients. Micro-fracture leads to significant cartilage regeneration only within small-sized lesions (2-4 cm2). Repair of even the small-sized lesions are limited by the age of the patients, as research shows that only patients under 40~50 years of age show cartilage regeneration. Furthermore, in cases of younger (less than 50-55 years old) patients with small-sized lesions, the regenerated cartilage does not show the histological components such as glycosaminoglycans (GAG) and collagen type II for hyaline-like (natural) cartilage, which are found in the articular surfaces of healthy knee joints. Some patients that have undergone this surgery have reported decreasing knee function after an initial increase in knee function for 1~1.5 years. In addition, this surgical method was also found to produce unpredictable results in some patients.
Joint replacement surgery: Joint replacement surgery is available in two forms – Partial Knee Replacement (“PKR”) and Total Knee Replacement (“TKR”). As the names for these procedures suggest, PKR only replaces certain parts of the affected knee. The knee is comprised of three major components: the medial compartment, the lateral compartment, and the patellofemoral compartment. Depending on the injury site and the severity of knee OSTEOARTHRITIS, the patient may opt for PKR because a small area of the knee is damaged. Regardless whether it is PKR or TKR, the surgical procedures are similar. Procedures for knee replacement (also called knee arthroplasty) are as follows: i) damaged articular cartilage on the surface of the femur and tibia are removed, with small bits of the underlying bones; ii) metal implants are inserted to recreate the surface of the joint, the metal implants may be affixed using cement or press-fit into the bone; iii) resurfacing the patella (kneecap) which is an optional step; and, iv) a medical-grade plastic spacer is inserted between the metal components on the femur and tibia, thus forming the simulated articular cartilage.
The major drawback of joint replacement surgery is the limited lifespan of the implant given the artificial joint. Because the implants generally last for 15 years at best, if the patients are in their late-40s to early-60s, they are generally not recommended for joint replacement surgery because of the lifespan of the implant. After that, it is almost impossible to perform a second joint replacement surgery. The fact that the CARTISTEM Phase III trial showed regeneration of cartilage in the patients of all ages including in their 50s, 60s and beyond, shows that CARTISTEM can meet the unmet medical need of those patients in that age group (i.e., late-40s,50s and early-60s). Furthermore, some PKR/TKR patients may develop immunological responses from prolonged periods of exposure to implant material. Also, a long-term rehabilitation regimen may be required post-operatively for joint replacement surgery patients.
ACI / matrix-induced ACI (“MACI”): ACI is one of the newer methods of treating cartilage defects of the knee. This method is recommended for patients who have sustained acute cartilage injury such as from sporting activities or accidents. The affected area of cartilage damage must not be over 3~4 cm2 with positive clinical outcome demonstrated only in patients less than 45 years of age. ACI (or MACI) utilizes cartilage tissue from the patient’s own injured knee which are surgically extracted using arthroscopic tools. The cartilage tissue is sent to a GMP facility where the cells extracted from the patient’s cartilage tissue are cultured and expanded. After a growing period, the cells capable of generating cartilage matrix known as “chondrocytes” are sent back to the clinic and surgically implanted back into the patient’s cartilage defect area. This method attempts to have these cultured chondrocytes grow to fill in the defects of the affected area in the hopes that these chondrocytes will form a new cartilage surface.
The limit on the age of the patient is also a major drawback of the ACI/MACI treatment because it uses the patient’s own cartilage tissue (from which the cartilage making chondrocytes are cultured). Past results have shown that only patients up to 45 years in age show cartilage regeneration following the ACI or MACI treatments. For this reason, the labels of commercially available ACI/MACI products read statements such as the following: “Clinical studies of [product name] did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.” Furthermore, even for the young patients who may be eligible for ACI/MACI treatment, the disease indication is restricted to “focal and/or isolated cartilage defects” (e.g., in the cases of sports injury or accidents) rather than degenerative osteoarthritis. The fact that the patient has to visit the clinic twice (once to provide cartilage tissue sample and again to receive cell treatment) is another disadvantage and may add costs for patients.
In contrast, CARTISTEM can be applied with a single visit to the clinic and can treat cartilage defects from injury/accidents as well as natural degeneration (as in the cases of osteoarthritis across all ages of patients. Another disadvantage associated with ACI/MACI is the potential unpredictability of cartilage growth. Some patients that have undergone ACI/MACI treatment have reported overgrowth of cartilage, which may lead to discomfort and/or pain in the knee area.
Bone Marrow Aspirate Concentrate (“BMAC”): The major motivation for BMAC procedures (aspirating the patient’s own bone marrow and fractionating the cells using centrifugation before injecting a certain fraction of cells back into the same patient’s knee joint) would be that it does not require any regulatory approval in most countries (i.e. the aspiration and injection of cells from and to the same patient can be performed at the discretion of the treating physician, as a “medical procedure”). However, a clinically meaningful efficacy in terms of alleviating the symptoms of the osteoarthritis from a non-expanded and poorly characterized autologous cell population remains doubtful with a possibility of regeneration of cartilage from such procedure being close to zero.
Using BMAC from the patient’s own bone-marrow tissue is of a particular concern for older patients (over the ages of 50-55 years) because in both micro-fracture (relying on the autologous cells released from the bone-marrow bleeding caused by creating holes on the cartilage defect) and ACI/MACI, which rely on the actions from the patient’s own cells, autologous cells from patients older than 50 to 55 years of age showed limited efficacy when compared to younger patients. For this reason, use of MSCs from fresh and young cord blood in CARITSTEM creates a significant and meaningful advantage, especially for the older patients (over 50 to 55 years of age).
Platelet Rich Plasma (“PRP”): Platelet-rich plasma (PRP) preparation is patient’s own blood plasma that has been enriched with platelets. The use of autologous peripheral blood (from which the PRP is obtained from) does provide an easy access to the physicians without any regulatory restrictions. While PRP has been used for a wide range of clinical indications, no data from any randomized controlled clinical trial is available for the intra-articular injection of PRP for the treatment of cartilage defects or osteoarthritis. While there are some anecdotal reports with positive results in alleviation of pain for a period of several months in osteoarthritis patients using autologous PRP injection, the treated patients were at an early stage of osteoarthritis. By the same token with all other autologous-based therapies, PRP may also be limited by the age of the patients. There is a lack of research evidence on treatment efficacy of PRP and important parameters such as preparation procedure, location and timing of injection, and amount of dosage to yield clinical efficacy have not been determined or established. The American Academy of Orthopedic Surgeons and WellCare Health Plans Inc. have announced that the PRP protocols should only be used in clinical trials and research, and that PRP is not recommended for the purposes of osteoarthritis treatment.