Regeneration in humans

Regeneration in humans is the regrowth of lost tissues or organs in response to injury. This is in contrast to wound healing, or partial regeneration, which involves closing up the injury site with some gradation of scar tissue. Some tissues such as skin, the vas deferens, and large organs including the liver can regrow quite readily, while others have been thought to have little or no capacity for regeneration following an injury.

Numerous tissues and organs have been induced to regenerate. Bladders have been 3D-printed in the lab since 1999. Skin tissue can be regenerated in vivo or in vitro. Other organs and body parts that have been procured to regenerate include: penis, fats, vagina, brain tissue, thymus, and a scaled down human heart. One goal of scientists is to induce full regeneration in more human organs.

There are various techniques that can induce regeneration. By 2016, regeneration of tissue had been induced and operationalized by science. There are four main techniques: regeneration by instrument;[1] regeneration by materials;[2][3] regeneration by drugs[4][5][6] and regeneration by in vitro 3D printing.[3]

History of human tissue

In humans with non-injured tissues, the tissue naturally regenerates over time; by default, new available cells replace expended cells. For example, the body regenerates a full bone within ten years, while non-injured skin tissue is regenerated within two weeks.[2] With injured tissue, the body usually has a different response. This emergency response usually involves building a degree of scar tissue over a time period longer than a regenerative response, as has been proven clinically[7] and via observation. There are many more historical and nuanced understandings about regeneration processes. In full thickness wounds that are under 2mm, regeneration generally occurs before scarring.[8] In 2008, in full thickness wounds over 3mm, it was found that a wound needed a material inserted in order to induce full tissue regeneration.[9][10]

Some human organs and tissues regenerate rather than simply scar, as a result of injury. These include the liver, fingertips, and endometrium. More information is now known regarding the passive replacement of tissues in the human body, as well as the mechanics of stem cells. Advances in research have enabled the induced regeneration of many more tissues and organs than previously thought possible. The aim for these techniques is to use these techniques in the near future for the purpose of regenerating any tissue type in the human body.

Regeneration techniques

Regenerating a human ear using a scaffold

By 2016, regeneration had been operationalised and induced by four main techniques: regeneration by instrument;[1] regeneration by materials;[2][3] regeneration by 3d printing;[3] and regeneration by drugs.[4][5][6] By 2016, regeneration by instrument, regeneration by materials and by regeneration drugs had been generally operationalised in vivo (inside living tissues). Whilst by 2016, regeneration by 3d printing had been generally operationalised by in vitro (inside the lab) in order to be built and prepare tissue for transplantation.[3]

By instrument

A cut by a knife or a scalpel generally scars, though a piercing by a needle does not.[1][11] In 1976, a 3 by 3cm scar on a non-diabetic was regenerated by insulin injections and the researchers, highlighting earlier research, argued that the insulin was regenerating the tissue.[4][5] The anecdotal evidence also highlighted that a syringe was one of two variables that helped bring regeneration of the arm scar.[4] The syringe was injected into the four quadrants three times a day for eighty-two days.[4] After eighty-two days, after many consecutive injections, the scar was resolved and it was noted no scar was observable by the human eye.[4] After seven months the area was checked again and it was once again noted that no scar could be seen.[4]

In 1997, it was proven that wounds created with an instrument that are under 2mm can heal scar free,[8] but larger wounds that are larger than 2mm healed with a scar.[8]

In 2013, it was proven in pig tissue that full thickness micro columns of tissue, less than 0.5mm in diameter could be removed and that the replacement tissue, was regenerative tissue, not scar. The tissue was removed in a fractional pattern, with over 40% of a square area removed; and all of the fractional full thickness holes in the square area healed without scarring.[12] In 2016 this fractional pattern technique was also proven in human tissue.[1]

With materials

Generally, humans can regenerate injured tissues in vivo for limited distances of up to 2mm. The further the wound distance is from 2mm the more the wound regeneration will need inducement. By 2009, via the use of materials, a max induced regeneration could be achieved inside a 1 cm tissue rupture.[2] Bridging the wound, the material allowed cells to cross the wound gap; the material then degraded. This technology was first used inside a broken urethra in 1996.[2][3] In 2012, using materials, a full urethra was restored in vivo.[3]

Macrophage polarization is a strategy for skin regeneration.[13] Macrophages are differentiated from circulating monocytes.[13] Macrophages display a range of phenotypes varying from the M1, pro-inflammatory type to the M2, pro-regenerative type.[13] Material hydrogels polarise macrophages into the key M2 regenerative phenotype in vitro.[13] In 2017, hydrogels provided full regeneration of skin, with hair follicles, after partial excision of scars in pigs and after full thickness wound incisions in pigs.[13]

By 3D printing

In 2009, the regeneration of hollow organs and tissues with a long diffusion distance, was a little more challenging. Therefore, to regenerate hollow organs and tissues with a long diffusion distance, the tissue had to be regenerated inside the lab, via the use of a 3D printer.[2]

Various tissues that have been regenerated by in vitro 3D printing include:

  • The first organ ever induced and made in the lab was the bladder, which was created in 1999.[14]
  • By 2014, there had been various tissues regenerated by the 3D printer and these tissues included: muscle, vagina, penis and the thymus.
  • In 2014, a conceptual human lung was first bioengineered in the lab.[15][16] In 2015, the lab robustly tested its technique and regenerated a pig lung.[15][16] The pig lung was then successfully transplanted into a pig without the use of immunosuppressive drugs.[15][16]
  • In 2015, researchers developed a proof of principle biolimb inside a laboratory; they also estimated that it would be at least a decade for any testing of limbs in humans. The limb demonstrated fully functioning skin, muscles, blood vessels and bones.[17]
  • In April 2019, researchers 3d printed a human heart.[18] The prototype heart was made by human stem cells but only to the size of a rabbit's heart.[18] In 2019, the researchers hoped to one day place a scaled up version of the heart inside humans.[18]
Gradations of complexity
Level 1Level 2Level 3Level 4
SkinBlood vesselBladderHeart
MuscleLiver
NailsPancreas
Penis

With printing tissues, by 2012, there were four accepted standard levels of regenerative complexity that were acknowledged in various academic institutions:

  • Level one, flat tissue like skin was the simplest to recreate;[3]
  • Level two was tubular structures such as blood vessels;[3]
  • Level three was hollow non-tubular structures;[3]
  • Level four was solid organs, which were by far the most complex to recreate due to the vascularity.[3]

In 2012, within 60 days it was possible, inside the lab, to grow tissue the size of half a postage stamp to the size of a football field. Most cell types could be grown and expanded outside of the body, with the exception of the liver, nerve and pancreas, as these tissue types need stem cell populations.[3]

With drugs

Lipoatrophy is the localised loss of fat in tissue. It is common in diabetics who use conventional insulin injection treatment.[4] In 1949, a much more pure form of insulin was, instead of causing lipoatrophy, shown to regenerate the localised loss of fat after injections in to diabetics.[4] In 1984, it was shown that different insulin injections have different regenerative responses with regards to creating skin fats in the same person.[5] It was shown in the same body that conventional forms of insulin injections cause lipoatrophy and highly purified insulin injections cause lipohypertrophy.[5] In 1976, the regenerative response was shown to work in a non-diabetic after a 3 x 3cm lipoatrophic arm scar was treated with pure monocomponent porcine soluble insulin.[5][4] A syringe injected insulin under the skin equally in the four quadrants of the defect.[4] To layer four units of insulin evenly into the base of the defect, each quadrant of the defect received one unit of insulin three times a day, for eighty-two days.[4] After eighty-two days of consecutive injections the defect regenerated to normal tissue.[4][5]

In 2016, scientists could transform a skin cell into any other tissue type via the use of drugs.[6] The technique was noted as safer than genetic reprogramming which, in 2016, was a concern medically.[6] The technique, used a cocktail of chemicals and enabled efficient on site regeneration without any genetic programming.[6] In 2016, it was hoped to one day use this drug to regenerate tissue at the site of tissue injury.[6] In 2017, scientists could turn many cell types (such as brain and heart) into skin.[19]

Naturally regenerating appendages and organs

Heart

Cardiomyocyte necrosis activates an inflammatory response that serves to clear the injured myocardium from dead cells, and stimulates repair, but may also extend injury. Research suggests that the cell types involved in the process play an important role. Namely monocyte-derived macrophages tend to induce inflammation while inhibiting cardiac regeneration, while tissue resident macrophages may help restoration of tissue structure and function.[20]

Endometrium

The endometrium after the process of breakdown via the menstruation cycle, re-epithelializes swiftly and regenerates.[21] Though tissues with a non-interrupted morphology, like non-injured soft tissue, completely regenerate consistently; the endometrium is the only human tissue that completely regenerates consistently after a disruption and interruption of the morphology.[21]

Fingers

In May 1932, L.H. McKim published a report describing the regeneration of an adult digit-tip following amputation. A house surgeon in the Montreal General Hospital underwent amputation of the distal phalanx to stop the spread of an infection. In less than one month following surgery, x-ray analysis showed the regrowth of bone while macroscopic observation showed the regrowth of nail and skin.[22] This is one of the earliest recorded examples of adult human digit-tip regeneration.[23]

Studies in the 1970s showed that children up to the age of 10 or so who lose fingertips in accidents can regrow the tip of the digit within a month provided their wounds are not sealed up with flaps of skin – the de facto treatment in such emergencies. They normally won't have a fingerprint, and if there is any piece of the finger nail left it will grow back as well, usually in a square shape rather than round.[24][25]

In August 2005, Lee Spievack, then in his early sixties, accidentally sliced off the tip of his right middle finger just above the first phalanx. His brother, Dr. Alan Spievack, was researching regeneration and provided him with powdered extracellular matrix, developed by Dr. Stephen Badylak of the McGowan Institute of Regenerative Medicine. Mr. Spievack covered the wound with the powder, and the tip of his finger re-grew in four weeks.[26] The news was released in 2007. Ben Goldacre has described this as "the missing finger that never was", claiming that fingertips regrow and quoted Simon Kay, professor of hand surgery at the University of Leeds, who from the picture provided by Goldacre described the case as seemingly "an ordinary fingertip injury with quite unremarkable healing"[27]

A similar story was reported by CNN. A woman named Deepa Kulkarni lost the tip of her little finger and was initially told by doctors that nothing could be done. Her personal research and consultation with several specialists including Badylak eventually resulted in her undergoing regenerative therapy and regaining her fingertip.[28]

Kidney

Regenerative capacity of the kidney has been recently explored.[29]

The basic functional and structural unit of the kidney is nephron, which is mainly composed of four components: the glomerulus, tubules, the collecting duct and peritubular capillaries. The regenerative capacity of the mammalian kidney is limited compared to that of lower vertebrates.

In the mammalian kidney, the regeneration of the tubular component following an acute injury is well known. Recently regeneration of the glomerulus has also been documented. Following an acute injury, the proximal tubule is damaged more, and the injured epithelial cells slough off the basement membrane of the nephron. The surviving epithelial cells, however, undergo migration, dedifferentiation, proliferation, and redifferentiation to replenish the epithelial lining of the proximal tubule after injury. Recently, the presence and participation of kidney stem cells in the tubular regeneration has been shown. However, the concept of kidney stem cells is currently emerging. In addition to the surviving tubular epithelial cells and kidney stem cells, the bone marrow stem cells have also been shown to participate in regeneration of the proximal tubule, however, the mechanisms remain controversial. Studies examining the capacity of bone marrow stem cells to differentiate into renal cells are emerging.[30]

Like other organs, the kidney is also known to regenerate completely in lower vertebrates such as fish. Some of the known fish that show remarkable capacity of kidney regeneration are goldfish, skates, rays, and sharks. In these fish, the entire nephron regenerates following injury or partial removal of the kidney.

Liver

The human liver is particularly known for its ability to regenerate, and is capable of doing so from only one quarter of its tissue,[31] due chiefly to the unipotency of hepatocytes.[32] Resection of liver can induce the proliferation of the remaining hepatocytes until the lost mass is restored, where the intensity of the liver's response is directly proportional to the mass resected. For almost 80 years surgical resection of the liver in rodents has been a very useful model to the study of cell proliferation.[33][34]

Toes

Toes damaged by gangrene and burns in older people can also regrow with the nail and toe print returning after medical treatment for gangrene.[35]

Vas deferens

The vas deferens can grow back together after a vasectomy–thus resulting in vasectomy failure.[36] This occurs due to the fact that the epithelium of the vas deferens, similar to the epithelium of some other human body parts, is capable of regenerating and creating a new tube in the event that the vas deferens is damaged and/or severed.[37] Even when as much as five centimeters, or two inches, of the vas deferens is removed, the vas deferens can still grow back together and become reattached–thus allowing sperm to once again pass and flow through the vas deferens, restoring one's fertility.[37]

Induced regeneration

There are several human tissues that have been successfully or partially induced to regenerate. Many fall under the topic of regenerative medicine, which includes the methods and research conducted with the aim of regenerating the organs and tissues of humans as a result of injury. The major strategies of regenerative medicine include dedifferentiating injury site cells, transplanting stem cells, implanting lab-grown tissues and organs, and implanting bioartificial tissues.

Bladder

In 1999, the bladder was the first regenerated organ to be given to seven patients; as of 2014, these regenerated bladders are still functioning inside the beneficiaries.[14]

Fat

In 1949, purified insulin was shown to regenerate fat in diabetics with lipoatrophy.[4] In 1976, after 82 days of consecutive injections into a scar, purified insulin was shown to safely regenerate fat and completely regenerate skin in a non-diabetic.[4][5]

During a high-fat diet, and during hair follicle growth, mature adipocytes (fats) are naturally formed in multiple tissues.[38] Fat tissue has been implicated in the inducement of tissue regeneration. Myofibroblasts are the fibroblast responsible for scar and in 2017 it was found that the regeneration of fat transformed myofibroblasts into adipocytes instead of scar tissue.[39][38] Scientists also identified bone morphogenetic protein (BMP) signalling as important for myofibroblasts transforming into adipocytes for the purpose of skin and fat regeneration.[39]

Heart

Cardiovascular diseases are the leading cause of death worldwide, and have increased proportionally from 25.8% of global deaths in 1990, to 31.5% of deaths in 2013.[40] This is true in all areas of the world except Africa.[40][41] In addition, during a typical myocardial infarction or heart attack, an estimated one billion cardiac cells are lost.[42] The scarring that results is then responsible for greatly increasing the risk of life-threatening abnormal heart rhythms or arrhythmias. Therefore, the ability to naturally regenerate the heart would have an enormous impact on modern healthcare. However, while several animals can regenerate heart damage (e.g. the axolotl), mammalian cardiomyocytes (heart muscle cells) cannot proliferate (multiply) and heart damage causes scarring and fibrosis.

Despite the earlier belief that human cardiomyocytes are not generated later in life, a recent study has found that this is not the case. This study took advantage of the nuclear bomb testing during the Cold War, which introduced carbon-14 into the atmosphere and therefore into the cells of nearby inhabitants.[43] They extracted DNA from the myocardium of these research subjects and found that cardiomyocytes do in fact renew at a slowing rate of 1% per year from the age of 25, to 0.45% per year at the age of 75.[43] This amounts to less than half of the original cardiomyocytes being replaced during the average lifespan. However, serious doubts have been placed on the validity of this research, including the appropriateness of the samples as representative of normally aging hearts.[44]

Further research has been conducted that supports the potential for human cardiac regeneration. Inhibition of p38 MAP kinase was found to induce mitosis in adult mammalian cardiomyocytes,[45] while treatment with FGF1 and p38 MAP kinase inhibitors was found to regenerate the heart, reduce scarring, and improve cardiac function in rats with cardiac injury.[46]

One of the most promising sources of heart regeneration is the use of stem cells. It was demonstrated in mice that there is a resident population of stem cells or cardiac progenitors in the adult heart – this population of stem cells was shown to be reprogrammed to differentiate into cardiomyocytes that replaced those lost during a heart tissue death.[47] In humans specifically, a "cardiac mesenchymal feeder layer" was found in the myocardium that renewed the cells with progenitors that differentiated into mature cardiac cells.[48] What these studies show is that the human heart contains stem cells that could potentially be induced into regenerating the heart when needed, rather than just being used to replace expended cells.

Loss of the myocardium due to disease often leads to heart failure; therefore, it would be useful to be able to take cells from elsewhere in the heart to replenish those lost. This was achieved in 2010 when mature cardiac fibroblasts were reprogrammed directly into cardiomyocyte-like cells. This was done using three transcription factors: GATA4, Mef2c, and Tbx5.[49] Cardiac fibroblasts make up more than half of all heart cells and are usually not able to conduct contractions (are not cardiogenic), but those reprogrammed were able to contract spontaneously.[49] The significance is that fibroblasts from the damaged heart or from elsewhere, may be a source of functional cardiomyocytes for regeneration.

Simply injecting functioning cardiac cells into a damaged heart is only partially effective. In order to achieve more reliable results, structures composed of the cells need to be produced and then transplanted. Masumoto and his team designed a method of producing sheets of cardiomyocytes and vascular cells from human iPSCs. These sheets were then transplanted onto infarcted hearts of rats, leading to significantly improved cardiac function.[50] These sheets were still found to be present four weeks later.[50] Research has also been conducted into the engineering of heart valves. Tissue-engineered heart valves derived from human cells have been created in vitro and transplanted into a non-human primate model. These showed a promising amount of cellular repopulation even after eight weeks, and succeeded in outperforming currently-used non-biological valves.[51] In 2021, researchers demonstrated a switchable iPSCs-reprogramming-based approach for regeneration of damaged heart without tumor-formation in mice.[52] In April 2019, researchers 3d printed a prototype human heart the size of a rabbit's heart.[18]

Lung

Chronic obstructive pulmonary disease (COPD) is one of the most widespread health threats today. It affects 329 million people worldwide, which makes up nearly 5% of the global population. Having killed over 3 million people in 2012, COPD was the third greatest cause of death.[53] Worse still, due to increasing smoking rates and the aging populations in many countries, the number of deaths as a result of COPD and other chronic lung diseases is predicted to continue increasing.[54] Therefore, developments in the lung's capacity for regeneration is in high demand.

It has been shown that bone marrow-derived cells could be the source of progenitor cells of multiple cell lineages, and a 2004 study suggested that one of these cell types was involved in lung regeneration.[55] Therefore, a potential source of cells for lung regeneration has been found; however, due to advances in inducing stem cells and directing their differentiation, major progress in lung regeneration has consistently featured the use of patient-derived iPSCs and bioscaffolds. The extracellular matrix is the key to generating entire organs in vitro. It was found that by carefully removing the cells of an entire lung, a "footprint" is left behind that can guide cellular adhesion and differentiation if a population of lung epithelial cells and chondrocytes are added.[56] This has serious applications in regenerative medicine, particularly as a 2012 study successfully purified a population of lung progenitor cells that were derived from embryonic stem cells. These can then be used to re-cellularise a three-dimensional lung tissue scaffold.[57]

Indeed, in 2008, there was a successful clinical transplantation of a tissue-engineered trachea in a 30-year-old woman with end-stage bronchomalacia. An ECM scaffold was created by removing the cells and MHC antigens from a human donated trachea, which was then colonised by epithelial cells and mesenchymal stem cell-derived chondrocytes cultured from cells of the recipient.[58] The graft replaced her left main bronchus, immediately providing a functional airway, and retained its normal appearance and mechanical function after four months.[58] Because the graft was generated from cells cultured from the recipient, no anti-donor antibodies or immunosuppressive drugs were needed—a huge step towards personalised lung regeneration.

A 2010 investigation took this one step further by using the ECM scaffold to produce entire lungs in vitro to be transplanted into living rats.[59] These successfully enabled gas exchange but for short time intervals only.[59] Nevertheless, this was a huge leap towards whole lung regeneration and transplants for humans, which has already taken another step forward with the lung regeneration of a non-human primate.[60]

Cystic fibrosis is another disease of the lungs, which is highly fatal and genetically linked to a mutation in the CFTR gene. Through growing patient-specific lung epithelium in vitro, lung tissue expressing the cystic fibrosis phenotype has been achieved.[61] This is so that modelling and drug testing of the disease pathology can be carried out with the hope of regenerative medical applications.

Penis

Penises have been successfully regenerated in the lab.[14] Penises are harder to regenerate than the skin, bladder and vagina due to their structural complexity.[14]

Spinal nerves

A goal of spinal cord injury research is to promote neuroregeneration, reconnection of damaged neural circuits.[62] The nerves in the spine are a tissue that requires a stem cell population to regenerate. In 2012, a Polish fireman Darek Fidyka, with paraplegia of the spinal cord, underwent a procedure, which involved extracting olfactory ensheathing cells (OECs) from Fidyka's olfactory bulbs, and injecting these stem cells, in vivo, into the site of the previous injury. Fidyka eventually gained feeling, movement and sensation in his limbs, especially on the side where the stem cells were injected; he also reported gaining sexual function. Fidyka can now drive and can now walk some distance aided by a frame. He is believed to be the first person in the world to recover sensory function from a complete severing of the spinal nerves.[63][64]

Thymus

The thymus gland is one of the first organs to degenerate in normal healthy individuals. Researchers from the University of Edinburgh have succeeded in regenerating a living organ that closely resembles a juvenile thymus in terms of structure and gene expression profile.[65]

Vagina

Between the years 2005 and 2008, four women with vaginal hypoplasia due to Müllerian agenesis were given regenerated vaginas.[66] Up to eight years after the transplants, all organs have normal function and structure.[14]

See also

References

  1. 1 2 3 4 Tam, Joshua (14 June 2016). "Reconstitution of full-thickness skin by microcolumn grafting". Journal of Tissue Engineering and Regenerative Medicine Research. Department of Dermatology, Harvard Medical School, Boston, MA, US: wileyonlinelibrary.com. 11 (10): 2796–2805. doi:10.1002/term.2174. PMC 5697650. PMID 27296503.
  2. 1 2 3 4 5 6 Atala, Anthony (October 2009). "Growing new organs". TED.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 McManus, Rich (2 March 2012). "Atala Surveys Successes of Regenerative Medicine". nihrecord.nih.gov. Archived from the original on 2014-11-21. Retrieved 7 April 2015.
  4. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Amroliwalla, F K. (25 March 1977). "Vaccination scar with soft-tissue atrophy restored by local insulin treatment". British Medical Journal. 1 (6073): 1389–1390. doi:10.1136/bmj.1.6073.1389. PMC 1606939. PMID 861647.
  5. 1 2 3 4 5 6 7 8 Campbell, W; Duncan, C; Anani, A. R. (1984). "Paradoxical lipodystrophic changes due to conventional bovine and highly purified porcine/bovine insulins". British Medical Journal. United Kingdom: pmj.bmj.com. 60 (704): 439–441. doi:10.1136/pgmj.60.704.439. PMC 2417884. PMID 6379631.
  6. 1 2 3 4 5 6 Smith, Dana G. (28 April 2016). "Scientists turn skin cells into heart cells and brain cells using drugs: Studies represent first purely chemical cellular reprogramming, changing a cell's identity without adding external genes". sciencedaily.com. Gladstone Institutes.
  7. ↑ Cubison TC, Pape SA, Parkhouse N (December 2006). "Evidence for the link between healing time and the development of hypertrophic scars (HTS) in paediatric burns due to scald injury". Burns. 32 (8): 992–9. doi:10.1016/j.burns.2006.02.007. PMID 16901651.
  8. 1 2 3 Wilgus, Traci A. (June 2007). "Regenerative Healing in Fetal Skin: A Review of the Literature". Ostomy Wound Management. 53 (6): 16–31, quiz 32-3. PMID 17586870.
  9. ↑ Dorin RP, Pohl HG, De Filippo RE, Yoo JJ, Atala A (2008). "A. World J. Urol. 2008; 26:323". World J Urol. 26 (4): 323–6. doi:10.1007/s00345-008-0316-6. PMID 18682960. S2CID 24808282.
  10. ↑ Anthony Atala; Darrell J. Irvine; Marsha Moses; Sunil Shaunak (1 August 2010). "Wound Healing Versus Regeneration: Role of the Tissue Environment in Regenerative Medicine". MRS Bull. 35 (8): 597–606. doi:10.1557/mrs2010.528. PMC 3826556. PMID 24241586.
  11. ↑ Joshua Tam (2013). "Fractional Skin Harvesting: Autologous Skin Grafting without Donor-site Morbidity". Plastic and Reconstructive Surgery. Global Open. Plastic & Reconstructive Surgery September 2013. 1 (6): e47. doi:10.1097/GOX.0b013e3182a85a36. PMC 4174164. PMID 25289241.
  12. ↑ Justin R. Fernandes, MD, Juan C. Samayoa, MD, G. Felix Broelsch, MD, Michael C. McCormack, MBA, Alexa M. Nicholls, BS, Mark A. Randolph, MAS, Martin C. Mihm, MD, William G. Austen, Jr., MD (2013). "Micro-Mechanical Fractional Skin Rejuvenation". Plastic and Reconstructive Surgery. PLASTIC SURGERY 2012. 131 (2): 216–23. doi:10.1097/PRS.0b013e3182789afa. PMID 23357983. S2CID 205973125.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. 1 2 3 4 5 Savoji, Houman; Godau, Brent; Sheikh Hassani, Mohsen; Akbari, Mohsen (26 July 2018). "Skin Tissue Substitutes and Biomaterial Risk Assessment and Testing". Frontiers in Bioengineering and Biotechnology. Front. Bioeng. Biotechnol. 6: 86. doi:10.3389/fbioe.2018.00086. PMC 6070628. PMID 30094235.
  14. 1 2 3 4 5 Mohammadi, Dara (4 October 2014). "Bioengineered organs: The story so far…". theguardian.com. Retrieved 9 March 2015.
  15. 1 2 3 Gonzalez, Robbie (8 January 2018). "Bioengineers Are Closer Than Ever To Lab-Grown Lungs". wired.com. Retrieved 27 May 2020.
  16. 1 2 3 Uriarte, Juan J (2018). "Lung bioengineering advances and challenges in lung decellularization and recellularization". Current Opinion in Organ Transplantation. journals.lww.com. 23 (6): 673–678. doi:10.1097/MOT.0000000000000584. PMID 30300330. S2CID 52946782.
  17. ↑ Plaugic, Lizzie (4 June 2015). "Researchers have grown a partially functioning rat limb in a lab". theverge.com. washingtonpost.com. Retrieved 8 June 2015.
  18. 1 2 3 4 Bracho-Sanchez, Dr. Edith (17 April 2019). "Researchers 3D-print heart from human patient's cells". edition.cnn.com. cnn. Retrieved 8 May 2019.
  19. ↑ ScienceDaily Staff (18 October 2017). "Turning brain cells into skin cells: Researchers transform mature cells from the brain, heart and more into skin cells". sciencedaily.com. American Friends of Tel Aviv University.
  20. ↑ Frangogiannis, N.G. (May 2015). "Inflammation in cardiac injury, repair and regeneration". Curr Opin Cardiol. 30 (3): 240–245. doi:10.1097/HCO.0000000000000158. PMC 4401066. PMID 25807226.
  21. 1 2 Min, Su; Wang, Song W.; Orr, William (2006). "Graphic general pathology: 2.2 complete regeneration". Pathology. pathol.med.stu.edu.cn. Archived from the original on 2012-12-07. Retrieved 2013-11-10. After the repair process has been completed, the structure and function of the injured tissue are completely normal. This type of regeneration is common in physiological situations. Examples of physiological regeneration are the continual replacement of cells of the skin and repair of the endometrium after menstruation. Complete regeneration can occur in pathological situations in tissues that have good regenerative capacity.
  22. ↑ McKim, L.H. (May 1932). "Regeneration Of The Distal Phalanx". The Canadian Medical Association Journal. 26 (5): 549–550. PMC 402335. PMID 20318716.
  23. ↑ Wicker, Jordan; Kenneth Kamler (August 2009). "Current concepts in limb regeneration: A hand surgeon's perspective". Annals of the New York Academy of Sciences. 1172 (1): 95–109. Bibcode:2009NYASA1172...95W. doi:10.1111/j.1749-6632.2009.04413.x. PMID 19735243. S2CID 22948936.
  24. ↑ Weintraub, Arlene (May 24, 2004). "The Geniuses Of Regeneration". BusinessWeek.
  25. ↑ Illingworth Cynthia M (1974). "Trapped fingers and amputated fingertips in children". Journal of Pediatric Surgery. 9 (6): 853–858. doi:10.1016/s0022-3468(74)80220-4. PMID 4473530.
  26. ↑ "Regeneration recipe: Pinch of pig, cell of lizard". NBC News. Associated Press. February 19, 2007. Retrieved October 24, 2008.
  27. ↑ Goldacre, Ben (May 3, 2008). "The missing finger that never was". The Guardian.
  28. ↑ Woman's persistence pays off in regenerated fingertip by Elizabeth Cohen. CNN website, September 9, 2010 4:51 p.m., page found 2010-09-16.
  29. ↑ Song Jeremy J (2013). "Regeneration and experimental orthotopic transplantation of a bioengineered kidney". Nature Medicine. 19 (5): 646–651. doi:10.1038/nm.3154. PMC 3650107. PMID 23584091.
  30. ↑ Kurinji; et al. (2009). "In Vitro Differentiation of MSC into Cells with a Renal Tubular Epithelial-Like Phenotype". Renal Failure. 31 (6): 492–502. doi:10.1080/08860220902928981. PMID 19839827.
  31. ↑ "Liver Regeneration Unplugged". Bio-Medicine. 2007-04-17. Retrieved 2007-04-17.
  32. ↑ Michael, Sandra Rose (2007). "Bio-Scalar Technology: Regeneration and Optimization of the Body-Mind Homeostasis" (PDF). 15th Annual AAAAM Conference: 2. Archived from the original (PDF) on November 20, 2008. Retrieved October 24, 2008.
  33. ↑ Higgins, GM; RM Anderson RM (1931). "Experimental pathology of the liver. I. Restoration of the liver of the white rat following partial surgical removal". Arch. Pathol. 12: 186–202.
  34. ↑ Michalopoulos, GK; MC DeFrances (April 4, 1997). "Liver regeneration". Science. 276 (5309): 60–66. doi:10.1126/science.276.5309.60. PMID 9082986. S2CID 2756510.
  35. ↑ DeMarco, Peter. 1986. Method of treatment of animal and human tissues damaged by burns and frank visible gangrene. US 4618490
  36. ↑ Miller, Korin (2017-09-11). "Here's What Happens When a Vasectomy Fails". SELF. Retrieved 2019-03-16.
  37. 1 2 Rolnick, H. C. (July 1924). "Regeneration of the Vas Deferens". Archives of Surgery. 9 (1): 188. doi:10.1001/archsurg.1924.01120070191008. ISSN 0004-0010.
  38. 1 2 Horsley, Watt (6 April 2017). "Repeal and Replace: Adipocyte Regeneration in Wound Repair". Cell Stem Cell (Submitted manuscript). 20 (4): 424–426. doi:10.1016/j.stem.2017.03.015. PMID 28388424.
  39. 1 2 Plikus; et al. (5 January 2017). "Regeneration of fat cells from myofibroblasts during wound healing". Science. 355 (6326): 748–752. Bibcode:2017Sci...355..748P. doi:10.1126/science.aai8792. PMC 5464786. PMID 28059714.
  40. 1 2 Mendis, Shanthi; Puska, Pekka; Norrving, Bo (2011). Global atlas on cardiovascular disease prevention and control (PDF) (1st ed.). Geneva: World Health Organization in collaboration with the World Heart Federation and the World Stroke Organization. pp. 3–18. ISBN 9789241564373.
  41. ↑ GBD 2013 Mortality and Causes of Death, Collaborators (17 December 2014). "Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013". Lancet. 385 (9963): 117–71. doi:10.1016/S0140-6736(14)61682-2. PMC 4340604. PMID 25530442. {{cite journal}}: |first1= has generic name (help)
  42. ↑ Laflamme, MA; Murry, CE (July 2005). "Regenerating the heart". Nature Biotechnology. 23 (7): 845–56. doi:10.1038/nbt1117. PMID 16003373. S2CID 8265954.
  43. 1 2 Bergmann O, et al. (2009). "Evidence for Cariomyocyte Renewal in Humans". Science. 324 (5923): 98–102. Bibcode:2009Sci...324...98B. doi:10.1126/science.1164680. PMC 2991140. PMID 19342590.
  44. ↑ Kajstura J, et al. (2012). "Response to Bergmann et al: Carbon 14 Birth Dating of Human Cardiomyocytes". Circulation Research. 110 (1): e19–e21. doi:10.1161/CIRCRESAHA.111.259721. PMC 4159170. PMID 25214670.
  45. ↑ Engel, F. B.; Schebesta, M.; Duong, M. T.; Lu, G.; Ren, S.; Madwed, J. B.; Jiang, H.; Wang, Y.; Keating, M. T. (2005). "P38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes". Genes & Development. 19 (10): 1175–1187. doi:10.1101/gad.1306705. PMC 1132004. PMID 15870258.
  46. ↑ Felix B. Engel, Patrick C. H. Hsieh, Richard T. Lee, Mark T. Keating; Hsieh; Lee; Keating (October 2006). "FGF1/p38 MAP kinase inhibitor therapy induces cardiomyocyte mitosis, reduces scarring, and rescues function after myocardial infarction". Proceedings of the National Academy of Sciences. 103 (42): 15546–15551. Bibcode:2006PNAS..10315546E. doi:10.1073/pnas.0607382103. PMC 1622860. PMID 17032753.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  47. ↑ Smart N, et al. (2011). "De novo cardiomyocytes from within the activated dult heart after injury". Nature. 474 (7353): 640–644. doi:10.1038/nature10188. PMC 3696525. PMID 21654746.
  48. ↑ Laugwitz KL, et al. (2005). "Postnatal isl1+carioblasts enter fully differentiated cardiomyocyte lineages". Nature. 433 (7026): 647–653. Bibcode:2005Natur.433..647L. doi:10.1038/nature03215. PMC 5578466. PMID 15703750.
  49. 1 2 Ieda M, et al. (2010). "Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes by Defined Factors". Cell. 142 (3): 375–386. doi:10.1016/j.cell.2010.07.002. PMC 2919844. PMID 20691899.
  50. 1 2 Masumoto H, et al. (2014). "Humans iPS cell-engineered cardiac tissue sheets with cardiomyocytes and vascular cells for cardiac regeneration". Scientific Reports. 6714: 6716. Bibcode:2014NatSR...4E6716M. doi:10.1038/srep06716. PMC 4205838. PMID 25336194.
  51. ↑ Weber B, et al. (2013). "Off-the-shelf human decellularized tissue-engineered heart valves in a non-human primate model". Biomaterials. 34 (30): 7269–7280. doi:10.1016/j.biomaterials.2013.04.059. PMID 23810254.
  52. ↑ Chen, Yanpu; Lüttmann, Felipe F.; Schoger, Eric; Schöler, Hans R.; Zelarayán, Laura C.; Kim, Kee-Pyo; Haigh, Jody J.; Kim, Johnny; Braun, Thomas (24 September 2021). "Reversible reprogramming of cardiomyocytes to a fetal state drives heart regeneration in mice". Science. 373 (6562): 1537–1540. doi:10.1126/science.abg5159.
  53. ↑ "The 10 leading causes of death in the world, 2000 and 2011". World Health Organization. July 2013. Retrieved November 29, 2013.
  54. ↑ Mathers CD, Loncar D (November 2006). "Projections of Global Mortality and Burden of Disease from 2002 to 2030". PLOS Med. 3 (11): e442. doi:10.1371/journal.pmed.0030442. PMC 1664601. PMID 17132052.
  55. ↑ Ishizawa K, et al. (2004). "Bone marrow-derived cells contribute to lung regeneration after elastase-induced pulmonary emphysemal". FEBS. 556 (1–3): 249–252. doi:10.1016/s0014-5793(03)01399-1. PMID 14706858. S2CID 1334711.
  56. ↑ Balestrini JL, et al. (2015). "Extracellular Matrix as a Driver for Lung Regeneration". Annals of Biomedical Engineering. 43 (3): 568–576. doi:10.1007/s10439-014-1167-5. PMC 4380778. PMID 25344351.
  57. ↑ Longmire TA, et al. (2012). "Efficient Derivation of Purified Lung and Thyroid Progenitors from Embryonic Stem Cells". Cell Stem Cell. 10 (4): 398–411. doi:10.1016/j.stem.2012.01.019. PMC 3322392. PMID 22482505.
  58. 1 2 Macchiarini P, et al. (2008). "Clinical transplantation of a tissue-engineered airway". The Lancet. 372 (9655): 2023–2030. doi:10.1016/S0140-6736(08)61598-6. PMID 19022496. S2CID 13153058.
  59. 1 2 Petersen TH, et al. (2010). "Tissue-Engineered Lungs for in Vivo Implantation". Science. 329 (5991): 538–541. Bibcode:2010Sci...329..538P. doi:10.1126/science.1189345. PMC 3640463. PMID 20576850.
  60. ↑ Bonvillain RW, et al. (2012). "A Nonhuman Primate Model of Lung Regeneration: Detergent-Mediated Decellurization and Initial In Vitro Recellularization with Mesenchymal Stem Cells". Tissue Engineering Part A. 18 (23–24): 23–24. doi:10.1089/ten.tea.2011.0594. PMC 3501118. PMID 22764775.
  61. ↑ Wong AP, et al. (2012). "Directed differentiation of human pluripotent stem cells into mature airway epithelia expressing functional CFTR protein". Nature Biotechnology. 30 (9): 876–882. doi:10.1038/nbt.2328. PMC 3994104. PMID 22922672.
  62. ↑ Kabu, S.; Gao, Y.; Kwon, B.K.; Labhasetwar, V. (2015). "Drug delivery, cell-based therapies, and tissue engineering approaches for spinal cord injury". Journal of Controlled Release. 219: 141–54. doi:10.1016/j.jconrel.2015.08.060. PMC 4656085. PMID 26343846.
  63. ↑ Quinn, Ben (21 October 2014). "Paralysed man Darek Fidyka walks again after pioneering surgery". The Guardian. Retrieved 26 October 2014. The 38-year-old, who is believed to be the first person in the world to recover from complete severing of the spinal nerves, can now walk with a frame and has been able to resume an independent life, even to the extent of driving a car, while sensation has returned to his lower limbs.
  64. ↑ Walsh, Fergus (21 October 2014). "Paralysed man walks again after cell transplant". BBC. Retrieved 26 October 2014.
  65. ↑ Blackburn, CC (April 2014). "Regeneration of the aged thymus by a single transcription factor". Development. 141 (8): 1627–1637. doi:10.1242/dev.103614. PMC 3978836. PMID 24715454.
  66. ↑ Walker, Peter (2014-04-11). "Vaginas grown in labs successfully implanted into girls with rare disorder". The Guardian.

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