Dr Richard Padbury, one of Lucideon's materials consultants, questions whether regenerative medicine will transform healthcare as we know it.
Imagine if we could cure diseases, rather than simply treat them? Regenerative medicine, according to its exponents, is a revolutionary approach that could potentially do just that, transforming the healthcare industry by improving patient outcomes and enabling long-term economic savings. So what is the outlook for regenerative medicine and what advances can we anticipate in the future? Let's take a look at some of the challenges and opportunities that this novel approach could take.
A diverse field, regenerative medicine is split between the interdisciplinary research pillars of gene therapy, gene editing, cell therapy and tissue engineering.
With gene and cell therapies, the focus is on offsetting or inactivating mutated genes and restoring certain cell types, respectively. Tissue engineering though uses scaffolds to support the attachment and proliferation of cells that can be implanted directly into a patient to regenerate damaged tissues.1 One of the holy grails of tissue engineering is the promise that researchers will one-day grow replacement organs to reduce the burden on transplant wait lists and prevent the need for lifelong anti-rejection medications.
While research in this area grows, with some proponents indicating that such capabilities are 'just around the corner,'2,3 we must question whether this objective is feasible and whether this is the right message to convey. No-one is arguing that the significant progress made in regenerative medicine has helped to expand our knowledge of the human body and how to treat disease. Is it misleading though to claim that organs grown in a laboratory are 'just around the corner'?
To successfully cultivate a fully functioning organ would require a precise replica of the biodiversity of each tissue that regulates the functions of a target organ. However, our underlying biology is extremely complex and consists of an intricate blend of proteins, carbohydrates, capillaries, vasculature, nerves and small molecules, collectively called the extracellular matrix (ECM). The ECM gives our tissues a vital mix of mechanical stiffness, nutrient exchange and cell signalling pathways from which cell-to-cell and cell-to-ECM interactions dictate normal tissue function. Are we able to produce scaffolds that can reproduce the precise organization, chemical complexity and vasculature to support the vast cell populations of a target tissue? Without this we would be unable to grow or print functional organs.
Researchers have though made great strides in the development of three-dimensional scaffolds and organoids, miniaturized and simplified versions of a tissue or organ, that come in the form of sheets or clusters of cells and tissue. Advances in bioprinting, microfluidics and fiber processing have enabled researchers to replicate these tissue structures at smaller scales. In the early 1980s, the pioneering work of Professor Ioannis Yannas demonstrated that certain tissues could be 'tricked' into spontaneously regenerating. This was achieved by blocking wound contraction and scar formation using configurational replicas of the desired tissue.4 Further research has demonstrated the development of scaffolds, containing ECM fragments and signalling molecules, seeded with cells and conditioned to form tissues in the laboratory, or implanted directly to recruit dormant stem cells and induce regeneration.5
So, progress is being made. But despite these promising advances there are natural forces that impose significant challenges on the development of more complex and large scale tissue structures.
There are many examples of regeneration in nature such as, salamanders and starfish that can incredibly regrow arms and tails. But the same remarkable examples of regeneration are limited in humans. The capacity of human skin to regenerate, and to a certain extent bones and the liver, is well known. However, these examples of regeneration are mostly restricted to superficial tissues or the result of a compensatory process that causes residual tissue to grow in size to counterbalance loss in function.6 By the time humans are born, pluripotent stem cells responsible for development are mostly replaced by mature cells, that can no longer divide, and somatic stem cells which help maintain and repair parts of the body where they are found. Consequently, the pathway for regeneration in other organs such as, the heart and spinal cord, are dormant and much more difficult to trigger.
There are other factors that impact healing and regeneration. Humans (and mammals) possess natural mechanisms that are still not fully understood such as, tissue remodelling and immune responses that can impact how an implant is accepted and incorporated into surrounding healthy tissues. However, every patient is different and may respond to treatment in diverse ways that are difficult to predict. Despite the development of patient-specific and prevasularized scaffolds,7, 8 which may help overcome this complication, research has shown that patient-matched stem cells can subtly mutate outside the body and trigger an immune response once re-implanted.9 In short, evolutionary processes may permanently impact variability in performance, regulatory hurdles and cost of tissue engineered devices independent of their scale, complexity or replication of what nature provided.
Based on data from the Alliance for Regenerative Medicine, there are approximately twenty tissue engineered devices approved around the world.10 The majority are marketed for orthopaedics and woundcare which is potentially related to lower regulatory barriers and product variability, but development of these devices was certainly not trivial. However, evidence from the market suggests that significant barriers persist. Cultures based on organoids and three-dimensional scaffolds have been developed by companies to research disease progression and test drug candidates in the laboratory.11 After commercial success in the pharmaceutical industry, these organizations have set their sights on transferring promising results to the development of tissue engineered medical devices. However, some efforts have led to significant variability of biological performance in preclinical studies that have crippled resources and resulted in significant cut-backs on research and development.12 There are other companies with similar backgrounds, using early successes in drug development to fund translational research in medical devices. Time will tell whether these new entrants suffer the same fates.
To successfully develop whole organs requires the replication of structures that can host billions of cells, multiple cell groups and include the thousands of miles of capillaries and vessels and biological components with precise resolution. Despite recent developments that have successfully incorporated blood vessels and ECM fragments, there's a number of factors stacked against these devices that are a small fraction of the scale of an entire organ. Even if these technologies can be scaled, human anatomy is incredibly complex and there are natural mechanisms that researchers are still working hard to understand which are amplified in the development of laboratory grown organs.
The market needs for advanced tissue cultures in pharmaceutical applications, such as toxicology and drug development, appear to be strong. Small scale devices that promote the native tissue environment for laboratory tests are ripe for these applications. But, for medical devices, open questions remain – can tissue engineered devices do better than the body's natural defences and is chemical complexity and precise organization necessary, or is it possible to work with nature and biology? While regeneration is mostly dormant, the immune system has evolved to protect humans from disease and injury. Research has revealed the role that certain immune components play on the advancement of disease such as, lung fibrosis13 and liver cirrhosis. The balance between pro and anti-inflammatory responses are also known to encourage healing, and in some cases, impact regeneration. This has resulted in the development of devices that attenuate the initial immune response towards healing and repair.14 Moreover, the development of immunotherapies have been developed to treat some cancers.15 Does this research open up new possibilities to develop immune-centric treatments, in harmony with our natural defences, to cure disease or develop devices that augment healthy tissues to restore function rather than replace them entirely? These treatments may not be around the corner just yet but, could impact patient outcomes in the future.
Regenerative medicine is, without doubt, an exciting and revolutionary approach to healthcare. There are challenges to be faced but, these endeavours can hopefully be met as our understanding of the human body and the science needed to find cures to disease expands and progresses.
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