The team is directed by Professor Anthony Hollander who is the Arthritis Research UK Professor of Rheumatology and Tissue Engineering. Most of the work of the group has been focused on developing methods for the treatment or prevention of osteoarthritis, (see below for further details). However in recent years our stem cell biology research has led us into new directions, capitalising on our growing understanding of how best to use adult stem cells in tissue engineering strategies.
In 2008 the team became involved in a project to create the world's first tissue engineered airway that was implanted into a patient in Spain, Claudia Castillo, thereby saving her life. A 6cm segment of tracheal tissue was engineered using Claudia’s bone marrow mesenchymal stem cells grown in Bristol and converted to chondrocytes (cartilage cells) by applying a technique adapted from the Hollander group's osteoarthritis research programme. Find out more about the world-wide press coverage of this project:
We are now attempting to use a similar tissue engineering approach to create a living vascular smooth muscle patch that can be implanted into children with congenital heart disease. This new project is in collaboration with Massimo Caputo in the University’s Bristol Heart Institute and is being funded by The James Tudor Foundation.
There are several types of stem cell and these can be divided into those derived from embryos (Embryonic stem cells), those derived from adult tissue (adult stem cells) and those derived from the reprogramming of adult cells so that they behave as if they were embryonic stem cells (induced pluripotent stem cells). Our work focuses on adult mesenchymal stem cells derived from bone marrow. We also collaborate with Dr. Kafienah's team on their embryonic stem cell research. Adult stem cells have an increased capacity to proliferate compared with differentiated (specialised) cells but this is nowhere near as extensive as with embryonic stem cells. They can differentiate into several cell types but (unlike embryonic stem cells) not into all cells of the body. The advantage of adult stem cells is that they are relatively easily obtained from a patient biopsy (e.g. of bone marrow, fat or muscle) and they are much easier to handle in tissue culture than embryonic stem cells or induced pluripotent cells.
Osteoarthritis is a degenerative disease of the articulating joints that leads to a loss of cartilage and changes to the underlying bone. The only treatments available for this chronic disease of ageing are use of pain-killing drugs and ultimately total replacement of the hip or knee with an artificial prosthesis. Early restoration of cartilage function by replacement of the damaged tissue with new cartilage engineered in the laboratory may alleviate symptoms in many patients and delay or prevent the need for joint replacement. We previously showed that we can tissue engineer cartilage with good biochemical and histological properties using bone marrow-derived mesenchymal stem cells even if these cells are isolated from elderly patients with advanced osteoarthritis. This makes it possible for us to consider treating patients using their own cells, so avoiding the risk of immune rejection of the engineered cartilage after it has been implanted. However we have reason to believe that some bone marrow derived mesenchymal stem cells are better able to create cartilage than others. With funding from the James Tudor Foundation we have addressed this problem by cloning individual stem cells from bone marrow and comparing them for their ability to make cartilage and in the genes encoding for proteins that appear on the cell membrane. In this way we are hoping to find a cell surface marker that could be used to pull out these more highly chondrogenic clones from the bone marrow so that they can be used as a defined population when treating individual patients.
The knee has two types of cartilage. The articular cartilage at the ends of the bones is the same as in other joints. The menisci are a pair of semi-lunar fibrocartilage "dampers" found in each knee. The meniscal cartilage is biochemically different from articular cartilage. When an athlete tears a cartilage it is usually a meniscus that has been damaged, leading to acute pain and joint dysfunction. The usual treatment is removal of the damaged part of the meniscus, which takes away the pain but dramatically increases the risk of osteoarthritis developing in the injured knee, often at an early age. If the tear can be healed, returning the meniscus to its original state, this should prevent the development of osteoarthritis. With funding from the Wellcome Trust we have developed a “Stem cell bandage” that is designed to be inserted into a meniscal tear and to drive a healing of the tear by migration of the stem cells between the two sides of the injury. This therapy is now being further developed through our spin out company, Azellon Cell Therapeutics and by a grant from the Technology Strategy Board. We intend to undertake a clinical trial using Cell Bandage starting in 2011.
Patients with osteoarthritis experience great pain that varies in intensity and comes and goes with time and depending on their daily activities. For the rheumatologists the progress of the disease can be measured either by asking the patient about their pain and joint function or by measuring the loss of cartilage and changes to the underlying bone that can be seen on X-Ray or MRI. Unfortunately it can take many years for these changes to be easily measured using imaging techniques and a major challenge for the field is to find a blood or urine marker of joint damage that can provide a way of measuring what damage is going on at any one time. This would provide good quality feedback to the patient and would enable researchers to measure the effects of new drug or cell therapy treatments with greater accuracy and in much shorter studies than would be required when using X-Rays. We have identified a component of cartilage collagen which is found at higher than normal levels in osteoarthritic cartilage and which accumulates in the urine, allowing us to measure it very easily. With funding from the Dunhill Medical Trust we have been investigating this biomarker of osteoarthritis and working out if it can be used as a routine method of monitoring the disease.