Pathfinder: How do cartilage injuries heal naturally? An experimental study in humans

Osteoarthritis is a very common disease of the joints, for which in the United Kingdom alone almost 9 million people have sought treatment. Osteoarthritis causes severe pain, stiffness and makes the patient less able to go about their daily physical activities. Osteoarthritis is a disease of the joint and affects the cartilage inside the joint and the bone at the joint. Many factors are known to increase the risk of getting osteoarthritis, or the rate at which it gets worse. Very important among these factors is an injury or a defect of the cartilage. More than 250 years ago, a famous surgeon presented a paper at the Royal Society of London explaining that cartilage, once injured, does not heal. Since those days, doctors and scientists have thought that this is indeed the case. Nobody was therefore surprised that having a cartilage injury or defect is so dangerous when it comes to osteoarthritis.

Research from the past 10 years is now throwing doubt on this old certainty. Researchers who took regular scans of volunteers over time noted that sometimes these defects come and then go. Surgeons often see these defects when they reconstruct a ruptured knee ligament, a common sports injury. A Japanese group of surgeons decided to look again after a year to see what had happened to these defects, and noted that about half of them had got better! Cartilage defects in human therefore can heal, but nobody knows how this works. A large number of doctors and surgeons are therefore trying to find out how it works, using animal experiments. But a human is not an animal. Besides the fact that we walk on two instead of four legs, the healing of these defects in humans seems far better than in animals.

For many years, our Centre has helped patients who have knee cartilage damage by using the patients' own cartilage cells to help repair areas of damaged cartilage. This form of treatment using the body's own cells is known as "cell therapy". The treatment starts by taking a piece of cartilage about the size of a peanut (10 mm) from the patient's knee. We never treat this defect, but if we look again after a year, this 10 mm defect has always healed, all by itself. This is therefore another example of a naturally healing cartilage defect. Because we create the defect and can then follow how it heals over time, it will form an ideal way to study cartilage healing in humans.

Our proposal is therefore to use our cell therapy patients as a human experimental model of natural cartilage healing. We plan to use a wide range of techniques to study, identify and quantify the way in which cartilage heals. These techniques include Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET), Computed Tomography (CT), visual inspection of the joint itself during knee joint surgery, examining biopsies of repair tissue down the microscope and measuring various kinds of molecules researchers think are important. MRI, PET and CT can show us where the cells that make new cartilage are active, how much new cartilage and bone have formed, if the new tissue fills the whole damaged area, how smooth the surface of the cartilage is and how well attached it is to the adjacent normal cartilage. Histology using the microscope and other specialised techniques can show the actual molecules which are present, how they are arranged and how the cells are behaving. Besides our cell therapy patients, where all defects heal, we will also study a group of ligament reconstruction patients with cartilage defects. Only half of those will heal, so we can compare between the groups and perhaps understand more about what controls natural cartilage healing.

Cartilage defects play an important role in the pathogenesis of osteoarthritis. This fits the conventional wisdom that cartilage, once injured, does not heal. However, conflicting evidence is emerging from longitudinal MRI studies showing that cartilage defects do sometimes heal naturally in humans. We have observed this ourselves in cell-therapy patients, in whom we create a fresh cartilage defect to harvest chondrocytes for cell-expansion, and invariably find this defect healed at repeat arthroscopy a year later. Such natural cartilage healing in humans is poorly explored and understood.

This study aims to fill the current gap in our understanding of mechanisms whereby knee cartilage defects heal naturally in humans. It will do so by fully characterising the natural repair process of articular cartilage, from the early inflammatory response, via the cell proliferation phase to the matrix maturation and remodelling phase.

The overall research plan is an experimental study in humans using two patient groups: experimental and control. In the experimental group a fresh chondral defect will be created, whereas patients in the control group will have an established chondral defect. The study will therefore compare natural cartilage healing between an acute and an established defect. The proposed study will build a complete picture of the healing response using an innovative mix of techniques, namely biomechanical assessment (gait analysis and joint stability), imaging (MRI and PET/CT), synovial fluid and plasma biomarkers, arthroscopy, immunohistochemistry, biochemistry and mathematical modelling. Taken together, these techniques will provide the pattern over time of the biomechanical, inflammatory, proliferative/apoptotic, cartilage tissue and bone tissue status during natural cartilage repair.

The most direct future beneficiaries from the research will be patients with cartilage and bone defects and/or early osteoarthritis. We expect that the data from the research will help to develop better strategies to either prevent the disease from progressing or to treat it at an early stage.

Practising surgeons and doctors will also benefit from the proposed research. Details on the natural healing process of cartilage injuries and defects will assist them in deciding on treatments, such as the need for an operative treatment, and help them explain to patients what happened to their knee.

The public bodies NICE (National Institute for Health and Care Excellence) and the NHS will also be beneficiaries of this work. Our team has contributed to past NICE assessments of Autologous Cell Implantation (ACI) and is contributing to the currently ongoing NICE assessment of this technique ("ID686: Autologous chondrocyte implantation for repairing symptomatic articular cartilage defects of the knee"). The NICE committee meetings have brought up an urgent need for more knowledge on the natural healing process of cartilage defects. The NICE committee feels that insight in the natural healing process is essential to properly assess the cost-effectiveness of ACI, or for that matter any cartilage repair technique. The advice from NICE has national weight, because it effectively decides which types of cartilage treatments the NHS will provide. However, increasingly NICE advice also carries international weight, because many countries are facing the same questions around cost-effectiveness without having a similar body to provide the required evidence.

Business and industry can benefit from the knowledge of natural cartilage healing that will arise from the proposed study. Although developing new treatments is not a direct objective of the study, the knowledge from it will hopefully help to develop innovative ways of promoting natural healing.

Another sector to benefit will be charities involved with patients with joint disorders. Arthritis Research UK, one of those charities, funds a clinical trial of cell therapy to treat cartilage defects at our Institution, involving many members of the proposed research team. Part of the investigative work in this trial is funded by the MRC, and the experimental group in the proposed study is made up of patients in this trial. Arthritis Research UK also funds the Arthritis Research UK Tissue Engineering centre, of which our Institution is part. Arthritis Research UK is very interested in cartilage healing and cartilage repair strategies. The proposed research will help the charity in advising the public and in devising their research strategy. Arthritis Care, another charity supporting people with arthritis, will also be interested in the results of our proposed research. These will help the charity in advising the public.