Introduction

Diseases of the musculoskeletal system impose a substantial burden on Western societies, which is ever increasing with ageing of the population. Amongst the diseases with most impact are osteoarthritis (OA) and chronic low back pain caused by intervertebral disc (IVD) degeneration, involving the cartilaginous tissues of these organs. Despite the severity of the problems, medical solutions currently are limited and consist mainly of highly invasive surgery that replaces or immobilises the joint. Treatment with therapeutic small molecules and biologicals is hampered by the limited inaccessibility of the joint and IVD.

Content

Therefore local administration of bioactive molecules is increasingly in focus, although still mainly by repeated administration. Using degradable biomaterials for intra-articular and intradiscal delivery, prolonged presence of therapeutics can be achieved without the need of repetitive injections. Local biomaterial-based drug delivery has several advantages. 1) High and effective local concentrations can be attained for a prolonged time period. 2) Systemic levels are low, offering a new lease of life to drugs that are effective but have unacceptable systemic side effects. 3) Less drug is needed, thereby greatly reducing costs (e.g. growth factors, antibodies). 4) Released drugs have direct access to the diseased tissue. Several polymer material platforms consisting of natural building blocks have been successfully applied to this end, in up to large animal models and even human patients. In particular the delivery of existing anti-inflammatory drugs. A solid body of preclinical evidence was generated on intra-articular release of celecoxib (CXB), an efficient anti-inflammatory drug that however attains insufficient joint fluid levels upon oral intake. This OA drug was delivered by a biomaterial platform that has already been used in human patients for other drug delivery applications. Safety, biocompatibility and long-term pain reduction of CXB-loaded biomaterials was demonstrated in rats and canine patients, with up to a dosage equivalent of 40% of a single oral dose for daily intake. Likewise a delivery formulation based on corticosteroids has been developed and tested in human clinical trials, although release was not sufficiently extended to reach the primary endpoint.

In addition to synthetic drugs, RNA-based interventions have great potency to counter the issues small molecule drug and recombinant protein treatments raise, for several reasons. 1) Small inhibitory RNA inhibits the production and activity of only one target protein, whereas mRNA delivery to the native tissue cell results in the production of one type of active protein, with native tissue posttranslational modifications. This allows precision treatment for patients with specific phenotypes; 2) RNA-based treatments pose no risk for integration into the cell’s DNA, as compared to viral or plasmid gene therapy, an important prerequisite in treatment of non-lethal chronic diseases; 3) RNA paves the way to treatment of diseases and disease processes mediated by so-called undruggable targets. 4) RNA synthesis is fully chemical and thereby cheaper than recombinant protein production and is receiving increased attention since the advent of COVID-19 vaccines. However, a major challenge consists of penetration of particles required for oligonucleotide and mRNA delivery, through the tight avascular extracellular matrix of articular cartilage and the IVD. Involvement of multiple disciplines will allow the development of technologies and tools to overcome these hurdles.