The University of Southampton

Author: Amanda Madrigrano Furlani

Morphogenesis, organoids, and regrown limbs: The power of self-organising tissues in regenerative medicine

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Figure 1 – My younger self’s camera roll was absolutely filled with bottom-up pictures of trees’ branches. This is just one of many examples

My first well-formed academic interest took shape in the form of bright-eyed awe at the beauty, diversity, and complexity of every life-form that I set sights on. How wonderful the pattern of that treeā€™s branches! I would wonder at the factors driving the formation of that pattern.

This might all seem to be getting away from the topic of tissue-engineering, but morphogenesis (how the shape of organisms arises during development) is of great relevance in research and the clinic! There are two main views of how development occurs, with the classical ā€˜mosaicā€™ view, in which cells obey a deterministic programme, their fates determined genetically, and the ā€˜regulativeā€™ view, in which cell-cell interactions and multidirectional information transfer affect the developmental trajectories of the cell, with evidence pointing that both have their place in different developmental stages, as the cells take in physical, electrical, and chemical cues to ā€œdecideā€ how to arrange themselves. The way that organs and tissues form is at the core of many regenerative medicine issues, from birth defects, to genetic diseases, to cancer. Contrary to the intuitive assumption that organisms with higher regenerative capacity would also have higher propensity for cancer due to their higher cell proliferation, they actually have lower cancer incidences, implying the competent morphogenetic pathways used for regeneration may also prevent cells from falling into the disorder which can lead to tumorigenesis.

Check out this video for more information on organoids!

Indeed, this ability of cells to self-organise into tissues and organs has been exploited in the form of organoids, mini 3D structures which can be derived from Embryonic Stem Cells (ESCs) and induced Pluripotent Stem Cells (iPSCs), which can have very similar functions to in vivo organs, having incredible potential for drug testing, disease models, and even the possibility of becoming an alternative for organ transplants, overcoming barriers such as long waiting times and tissue rejection in patients; an organ grown from the patientā€™s own iPSCs, maybe edited genetically into a healthy form if applicable. This might even be an alternative to xenotransplants, bypassing several of the ethical issues associated with using animals for organ harvesting. Of course, organoids come with their own suite of ethical concerns, from source of the stem cells to the moral and legal status of organoids, especially in the cases of multi-organ and brain organoids, but the benefits of organoid research are worth the extra necessary steps to ensure such research follows our moral values.

Figure 2 – Adapted from Murugan et al, this table shows the regeneration of Xenopus laevis legs over a period of 18 months under different treatment conditions. From top to bottom, the treatment groups were no intervention, bioreactor dome but no cocktail, and biodome in combination with the drug cocktail.

And if that sounds fantastical, imagine my surprise when I found this property of cells could lead to the possibility of replacement limbs, not in the form of prostheses or even grown on scaffolds, but grown by the patient themselves! Over the course of a 2022 study, Murugan et al were able to trigger the regrowth of frog legs with the use of a bioreactor which served to protect the site of injury and deliver a drug-cocktail which, among other things, prevented growth of scar tissue by inhibiting collagen and encouraged nerve, muscle growth, and vascularisation, activating the bodyā€™s own regenerative abilities and molecular pathways used during embryonic development. Over the next 18 months, the frogs subjected to the 24-hour treatment grew back almost fully functional legs which they could stand and swim with. Of course, this technology is a long way away from clinical application, with mice being currently used to test whether this approach would even work in mammals. This, and other techniques discussed here, are yet in their infancy, with much of the basic groundwork yet to be done. Still, the future landscape of regenerative medicine holds many incredible possibilities that I am excited to witness.

Implications and Challenges in Animal and Wildlife Prosthetics

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From internal procedures like knee or hip joint replacements, to external ones like replacement limbs, prosthetics allow hundreds of thousands of people each year increased quality of life and mobility. As someone with a background in animal ecology, I became interested in how prosthetics for animals might be created; they have very different morphology and requirements to humans, with stronger forces being exerted on them, and the animalā€™s natural behaviour needs to be considered.

One example of prosthetics being used for non-human patients is, of course, Prof. Noel Fitzpatrick, who treats pets around the UK, for example Oscar, a cat who lost his hind limbs, and had them replaced with Intraosseous Transcutaneous Amputation Prosthetics (ITAP), where holes are drilled into the residual limbā€™s bone and the implants are then attached, allowing the skin to bond to the prosthetic, creating ā€˜pegsā€™ onto which the limb itself can then be attached following a recovery period. Similar methods for bone-anchored limb prosthetics are being considered for humans, though still in its early stages. Even a recent study performed on 16 cats and 4 pigs finds issues with infection at the stoma, and a high failure rate of integration. Regardless, it is true that prosthetic techniques being developed in the field of veterinary science can have implications for human medicine.

Figure 1 (Supervet, 2009) – Oscar the cat with his Osseointegrated hind limbs. Note the interaction between the patient’s skin and the limb.

But what I was most interested in was wild animals, whose requirements would be a lot different to petsā€™. Thatā€™s how I ran into Winter, a bottlenose dolphin whose tail was lost in a crab trap in 2005. Over a year and a half later, with a lot of work from a dedicated team, a prosthetic tail was completed and fitted onto Winter. Unlike an arm or a leg, a tail canā€™t simply stay solid as the animal moves, but must move along with it, hold its position under water and under the force of a large animal using it to propel its movement, not cause further injuries to Winter, and, of course, perform its function as a tail. The resulting material created from this research, WintersGel, can now be used for human patients, especially athletes as it is softer and distributes weight more evenly than other liners, reducing pain and pressure exerted by the limb.

Video of Winter’s tail prosthesis being fitted, showing some of the process of adapting to he new limb

There are many other cases of prosthetics being used in wildlife, from an injured Bald Eagle with a prosthetic beak, to a young elephant with a prosthetic foot, to a 3D-printed leg for a Secretary Bird at a bird park who injured her leg, and, prevented from engaging in her natural behaviours, began engaging in behaviour associated with poor welfare. There has even been a tiger in east Germany who, experiencing pain from arthritis, had a hip replacement, although a more recent operation hasnā€™t been as successful, and the tiger who underwent it had complications. This, as well as other cases where operation may have had more negative than positive consequences for the animal, raise the importance of ethical considerations in wildlife prostheses. Are these operations always necessary? Do they increase the animalā€™s quality of life, or do they add unnecessary stress to an animalā€™s life who might not survive for very much longer, or who, unable to engage in their full behavioural repertoire, might exhibit stereotypies or other negative behaviours? With humans, we can operate on the basis that each of us should have autonomy over what happens to our own bodies, and that informed consent is crucial in these and other procedures, but who should get to decide when the patient can neither understand what is happening nor communicate their preferences on the matter?

UOSM2031 Practice blog

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Hello! I’m Amanda, I’m a 3rd year Natural Sciences student who focuses mostly on ecology, using bioinformatics to find relationships between environmental factors and animal behaviour, especially in marine environments and with a seascape framework.

However, I started out being more interested in genetics and evolution, and especially in how animals’ body plans evolved and developed, and how by simply following a set of local rules, undifferentiated cells could develop into such complex morphologies, and “endless forms most beautiful”. I hope that with this module I can explore this side of my interests while also adding context to my current ones.