The long-held vision of tissue engineering is to grow functional organs in a lab, offering a solution to both the short supply of donor organs and the need for immunosuppressive transplant medications. That vision has been built on the premise of creating an intricate scaffold, seeded with cells that can be incubated over time to generate a complete organ in form and function, ready for implantation in the body. The organs classically pursued with this approach have been the heart, kidney, liver, and airway – among others – reflecting those in critical need of addressing the limited supply of internal organ donors.
After decades of pursuit, few approaches have made enough progress to reach the clinic in a meaningful way. In a quiet and determined effort, skin is emerging as a potential leader in regenerative medicine that could pave the way for new approaches in the field. With an epidemic of wounds impacting the world, and skin being the largest organ of the body with the innate ability to regenerate itself, it should come as no surprise that skin regeneration is beginning to champion the field. Equally intriguing is that skin regeneration might be accomplished with approaches that diverge from the original tissue engineering concepts of growing fully formed organs in a lab.
Challenges with Internal Organ Engineering
Four major challenges have emerged with engineering internal organs, including (1) a lack of innate regenerative ability, (2) the complexity of engineering a complete vascular network, (3) multiple different and delicate culture conditions required to incubate different cell populations, and (4) a lack of access to source material. Most internal organs do not have an innate ability to regenerate, which makes the endeavor exceedingly challenging without a model to replicate – and without an obvious cell source to utilize.
Healing exists on a continuum from scarring and fibrosis to scarless regeneration. When an organ tends to heal through fibrosis, there is no natural model of regeneration to replicate and scale up in the lab, making every approach uncharted territory. Without an existing model of regeneration to replicate, many of the fundamental questions remain unanswered, such as which cell types are capable of regenerating each part of the organ, what balance of those cell populations is needed to begin the growth process, what culture conditions are required for each cell population, and how can that all be coordinated to result in highly intricate functional outcomes like the electrical impulses that power each heartbeat.
The next major obstacle is integrating a functional vascular system into the organ prior to implantation. Engineering a functional vascular system to carry blood from a source artery into a capillary bed and back out a draining vein represents a massive undertaking in and of itself. On top of growing the organ’s native architecture and functional units, the functional vascular system needs to be integrated so that the lab-grown organ can sustain itself within a patient – perhaps representing the greatest challenge to achieving the vision of tissue engineering. Furthermore, all those pieces need to be brought together in a single process – regenerating functional units of an organ and regenerating an independent vascular network.
Every cell type thrives best in different culture conditions, and slight perturbations in those conditions can cause changes to the cells. Thus, another obstacle is encountered in designing an incubation system that can foster the regeneration of everything together in one place. Whether the process starts separately to be brought together at the end, or the process allows for each part to grow together, there is significant work to be done that will differ for each organ.
Finally, there remains the inherent challenge of a lack of healthy source material to start with from each patient. When an organ needs to be replaced, the damaged or diseased organ may not have a reliable supply of healthy cells to start the engineering process. For example, a fibrotic liver may not be able to serve as a starting source of cells to regenerate a new liver. This has driven some to pursue approaches using other cell types or stem cell sources as the starting material, but this makes all the other obstacles even more challenging. None of these obstacles are insurmountable, and we certainly should not slow our enthusiasm for pursuing the vision of lab-grown organs, but other approaches and other organs and tissues may lend themselves to success not originally conceived.
Recent Wins in Organ Replacement – Gene-Editing Animal Organs
In a much different approach compared to generating an engineered organ in the lab from the ground up, there have been recent successes with gene-edited pig kidneys transplanted into humans. A team from Massachusetts General Hospital has performed multiple xenotransplants using gene-edited pig kidneys. To remove pig genes and add human genes to make the kidneys more compatible, 69 genomic edits were made using CRISPR/Cas-9. The surgeries were performed under an Expanded Access Program through the FDA, with the pig kidneys provided by eGenesis, a company co-founded by Harvard Medical School geneticist George Church. The pig kidney recipients still require immunosuppressive regimens like human donated kidneys. This approach marks a novel departure from the concept of seeding a scaffold with the patient’s own cells to grow a complete organ in the lab, and also highlights the challenges with engineering a complete organ with the traditionally envisioned approach.1
Why Might Skin Become the Leading Organ for Regenerative Medicine?
Chronic wounds have turned into a worldwide epidemic with staggering statistics. A new diabetic foot ulcer forms every 20 seconds and a new amputation due to a diabetic foot ulcer occurs every three and a half minutes in the United States. Patients who lose their limb due to diabetic foot ulcers have a five-year mortality comparable to cancer. Given the massive need for wound healing solutions –and several advantages to regenerating skin compared to internal organs –skin may be poised to emerge as the leading organ to benefit from regenerative medicine.
Until the secrets of the immune system are solved, using the patient’s own cells and tissue remains the best option for regenerative approaches attempting to permanently replace a damaged or diseased organ. Skin is the largest organ of the human body and there is typically an area of healthy, unaffected skin that can serve as a source material for regenerative approaches. Skin also has an innate ability to regenerate itself, replacing the top layer of skin (epidermis) every month in adults and healing thousands of minor injuries throughout a lifetime. In fact, traditional split-thickness skin grafts are possible because only the top layer of skin is removed, and the deeper layers of skin left behind are capable of completely regenerating the top layer – similar to what everyone who healed a scraped knee has experienced. In addition, the regenerative process that ensues following injury to the skin has been fairly well mapped out, including the key cell populations, their locations, and their markers. The skin is rich in stem cell populations, including epidermal stem cells, dermal stem cells, fat-derived stem cells, and potent populations in the hair follicles and glands.
Not only does skin provide access to healthy, unaffected source material to create therapies leveraging the patient’s own skin (autologous therapies), but wounds also create a unique environment that is accessible for regeneration. Few, if any, other organs in need of regenerative therapies provide the opportunity for direct engraftment of the therapy the way wounded skin does. As learned through traditional skin grafting, engineered skin therapies do not necessarily have to have an intact vascular network for implantation. Skin grafts heal through engraftment, initially garnering nutrients and disposing of waste through the wound fluid before making direct connections to vessels within the wound bed, followed by new vessel formation sprouting and growing within the graft. Leveraging the natural formation of a blood supply through engraftment, the field of skin regeneration can focus on the complexities of skin without needing to also engineer a complete vascular network. Furthermore, skin regeneration therapies may not need to achieve final form in the lab before implantation due to the ability of the wound environment and engraftment process to support further maturation and growth of the therapy following application, ultimately letting the patient’s body complete the process with a therapy implanted at an earlier stage than possible with internal organs.
Hurdles to Overcome for Skin Regeneration
Despite the advantages skin may hold for regenerative medicine compared to other organs, hurdles remain to be overcome to change the approach to wound healing. Regulatory barriers remain the first step for any developing technology that shows promise. Clinical evidence of safety and efficacy must be proven through the stringent Biologics License Application (BLA) pathway with the FDA. In undertaking the process to seek regulatory approval, a manufacturing process must be developed that is scalable, cost-effective, and fits into timelines for clinical workflow. Overcoming regulatory and scalable manufacturing obstacles begins the next phase of evolution for any new medical technology to produce evidence that gains both payer coverage and clinical adoption.
Conclusion
The field of regenerative medicine may be on the cusp of an evolution, and due to the unique attributes of skin and wounds, the largest organ in the body may be emerging as a leader. Whichever organ manages to lead the charge, all boats will rise together and pave the way for advances across the board.
Editor’s Note: Ned Swanson, MD is the President & Chief Medical Officer of PolarityBio with a background in surgical innovation and biomedical engineering. He previously served as Co-Founder & Chief Medical Officer of PolarityTE from 2016 to 2021. Dr. Swanson received his MD from Harvard Medical School and completed his residency in Plastic Surgery at Johns Hopkins. His foundational expertise is rooted in Bioengineering from the University of Pennsylvania.
References
- https://hms.harvard.edu/news/surgeons-perform-second-pig-kidney-transplant-massachusetts-general-hospital