The recent technological advancements and the launch of the first phase of Artemis I on November 16^th 2022, are making a human return to the Moon and a first manned mission to Mars increasingly feasible. The most recent plans detailed by NASA in 2022 highlighted the need for an integrated, multi-system approach to allow an international campaign of human-led exploration on the Moon, and as a testbed for a mission to Mars, that also ensures a safe return to Earth. The key scientific targets are the establishment of a laboratory at the lunar South Pole, which will facilitate a package of experiments in life sciences designed to help with understanding the biological effects on human physiology and disease during short and long duration missions, whilst also gaining new scientific information to guide system development. Finally, a requirement was identified for technologies that would monitor crew health and provide medical care in these environments.

 However, human physiology is greatly adapted to the gravitational environment on Earth and the absence of this stimulus -in the low Earth orbit- or reduction -in a planetary setting such as the Moon or Mars- can have profound effects even during short sojourns. Some of the most immediate changes are in the cardiovascular system (caused by a shift of fluid to the upper part of the body), as well as a rapid reduction in tissue mass and structure in muscular and skeletal sites adapted to counteract the gravitational force during standing or locomotion.

Sustaining a presence on these celestial bodies will, however, require lengthy sojourns. The loss in tissue mass and structure during this time is, based on current knowledge, likely to increase proportionally with longer durations spent in reduced gravity. Although tissue deterioration may be slowed down by the presence of partial gravity (the Moon and Mars have approximately a sixth and third of Earth’s gravity), it is possible that the loss of skeletal mass and demineralisation during the transfer period might increase the risk of damage shortly after landing on Mars. This will clinically manifest as a loss of tissue in essential skeletal regions, increasing bone fragility and potentially compromising the ability to withstand re-entry forces on return. Maintaining skeletal integrity is also essential for performing any type of mechanical task, such as surface and extra-vehicular operations. On arrival, setting up a base will likely require lifting and moving weights and equipment during construction.

Whilst a whole range of countermeasures such as exercise, negative pressure application and dietary supplements has been incorporated in space missions over the past decades, with varying levels of success, considerations to mitigate tissue and organ damage on-site are equally important in the short-term and would need to be assessed simultaneously. This is particularly important for clinical contexts such as tissue rupture and dislocation, bone fractures, skin burns, abrasion or lacerations, tendon/ligament tears, and blood loss. Some of the reported tissue damage situations in space have involved small traumatic injuries to both the skin and mucous membranes, many involving hand injuries during translation between modules, resistive exercise and extra-vehicular activity components. However, major trauma is a strong possibility during deep-space exploration and long-duration spaceflight.

A shift towards autonomous medical support

Habitats further than the low-Earth orbit will not likely benefit from receiving supplies or assistance from Earth in emergency-type situations. In addition, there is a significant communication latency between Mars and Earth, that can range between 5-20 minutes depending on planetary positions. It is therefore unlikely that crews can rely on intermittent communications in those situations where expert medical support will be required immediately. Therefore, it will be essential that the facilities to mitigate damage, particularly significant trauma or injury, are present on-site. Under normal clinical circumstances, tissue reconstruction or replacement is performed using a combination of medical and bioengineered solutions, which range from metallic implants and deproteinised xenografts to tissue engineered autologous cell-containing matrices, which can be customised to replace the deteriorated tissue.

Building a deep-space biomedical habitat to address the physiological challenges and medical emergencies

Crews will require access to a sustainable source of tissue substitutes, biochemical scaffolds, haemostatic agents, or biomaterials such as dental fillers, in addition to specialised medical-surgical training in order to address a wide range of health challenges, from minor tears to serious emergencies. The need for quick recovery of function means that some form of tissue replacement/analogue would have to be developed on-site in useful time, implanted or applied to the injured site shortly after, or incubated (in the case of biological implants) as with typical procedures until a desired morphology/maturation stage is achieved.

The repair and reconstruction process will, in turn, require specialised equipment and considerations that have to match safety and efficiency with sustainability and practicality from a space hardware perspective. In addition, these biological-surgical-rehabilitation facilities would have to be located in proximity to each other due to many operational factors.

Habitat design considerations

The paper (Iordachescu et al., 2023) provides an extensive assessment of the requirements of a multi-module habitat that would support biomedical and clinical operations and allow both tissue substitute development (acellular and cellular) and surgical interventions, as well as recovery. This article provides highlights of the topics covered in the work.

From a bioengineering and clinical perspective, it is likely that in the short-term, traditional tissue reconstruction methodologies will be used to manage emergencies in deep-space (2030-2035), involving casting and hand mixing of suitable matrices, which are easier to implement in a spaceflight scenario. Surgical reconstruction options will be likely be initially focused around isolating and transferring minor autografts to the injured site as well as acellular, physically-treated scaffolds with native geometry and biochemistry (throughout 2040s). With further development of tissue engineering and 3D biofabrication technologies over the following years, more complex, personalised tissues and ultimately organ-like structures could be generated in an isolated environment (2040s-2050s) (Figure 1). Bioengineered organs are currently in early phases of development and will be essential in the initial mission stages for use as complex research platforms as opposed to regenerative medicine. These platforms include translational investigations into the effects of environmental conditions on tissue architecture and organ functions. While representing simplified versions of the in vivo structures, they can recapitulate many aspects of tissue architecture and biochemistry, which is ideal for bioengineering research and could be implemented within the required lunar and Mars mission timeframes.

Biofabrication is considered to be an essential enabling technology for in-space manufacturing, allowing the production of needed parts in useful time, including engineered tissues. However, biofabrication of tissues is still in early phases of development and furthermore, the generation of complex or large-scale tissues in a challenging gravitational environment, would require a form of support matrix to prevent movement and the failure of structures, particularly at interfaces.  The ability to produce constructs which can maintain integrity in reduced gravity is essential to this process, hence why support matrices will be required, such as polymeric fluid gel baths, which are increasingly used in tissue engineering (Figure 2). These would aid in traditional biofabrication in a hypogravity environment, acting as a temporary support matrix, which would allow the spatial deposition of the template, whilst self-healing around the print and acting as a suspending matrix from which the constructs can be easily recovered.

Operating theatre and surgical tool design will also have to be concomitantly assessed and adapted to the challenging gravitational conditions of these planets. Aspects such as a fluid containment kit, restraining equipment to prevent patient falling/drifting during operation, surgical tool adaptation and integration of X-ray/Ultrasonographic kit for assessing outcomes, will be critical.

Finally, processing of local resources will be key for generating laboratory and medical infrastructure. The Moon and Mars in particular, contain an abundance of resources in multiple forms, which can be extracted or converted into useful products to generate laboratory-specific reagents and tools.

From an operational perspective, one of the main challenges with the construction of such a critical habitat at a planetary surface is the exposure to significant cosmic radiation, as well as falling micro-meteorites and larger objects, which can significantly damage key structures. As such, additional geological environments may be a likely option for shielding, such as the lunar caverns or extensive Martian underground pyroducts. Mars, for example, contains many extensive caves and lava tubes that formed following previous volcanic activity (Figure 3). These structures are larger than the Earth counterparts and in the case of lunar caverns, these are believed to have more hospitable temperatures.

In conclusion, implementation of a life support infrastructure to ensure crew health, a sustained presence on the planetary surface and mission continuity will require a coordinated biomedical and clinical activity on-site, during multiple phases of increasing complexity, to mitigate the risks associated with the hazardous environments and operational tasks.  Over the next years, it will be essential to generate further predictions on these matters, which will ultimately dictate the design of these space settlements and the technology required to support these.