Nanogel

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Nanogel 

A nanogel is a polymer-based, crosslinked hydrogel particle on the sub-micron scale. These complex networks of polymers present a unique opportunity in the field of drug delivery at the intersection of nanoparticles and hydrogel synthesis. Nanogels can be natural, synthetic, or a combination of the two and have a high degree of tunability in terms of their size, shape, surface functionalization, and degradation mechanisms. Given these inherent characteristics in addition to their biocompatibility and capacity to encapsulate small drugs and molecules, nanogels are a promising strategy to treat disease and dysfunction by serving as delivery vehicles capable of navigating across challenging physiological barriers within the body.

Nanogels are not to be confused with Nanogel aerogel, a lightweight thermal insulator, or with nanocomposite hydrogels (NC gels), which are nanomaterial-filled, hydrated, polymeric networks that exhibit higher elasticity and strength relative to traditionally made hydrogels.

Synthesis

The synthesis of nanogels can be achieved using a vast array of different methods. However, two critical steps typically included in each method are polymerization and crosslinking, with physical and chemical crosslinking the most common. These steps can be completed concomitantly or in sequential order depending on the synthesis method and eventual nanogel application. Here, several different synthesis mechanisms are described briefly.

Graphical representation of seven different methods of synthesizing polymeric nanogels. Created with BioRender.

Desolvation/Coacervation and Precipitation 

In desolvation or coacervation, a non-solvent is added to a homogeneous polymer solution to produce individual, nanosized polymer complexes dispersed in the same solution. These complexes then undergo crosslinking to form nanogels with surface functionalization an optional next step.

In precipitation, initiators and crosslinking agents are added to a homogenous monomer solution to induce a polymerization reaction. When the polymer chain reaches the desired length, the reaction is halted and a polymer colloidal suspension is formed. Surfactants are the final addition to produce nanosized polymers.

Electrostatic and Hydrophobic Interactions

Electrostatic interactions can form nanogels through the combination of anionic and cationic polymers in an aqueous solution.  The size and surface charge of the resulting nanogels can be modulated by changing the molecular weight or the charge ratio of the two different polymers. Ionotropic gelation can also leverage electrostatic interactions between multivalent anions and cations to form nanogels.

Hydrophobic interactions rely heavily on physical crosslinking to form nanogels. In this method, hydrophobic groups are added to hydrophilic polymers in an aqueous solution to induce their self-assembly into nanogels.

Inverse-emulsion

Inverse-emulsion, or reverse miniemulsion, requires an organic solvent and a surfactant or emulsifying agent. Nanosized droplets are produced when an aqueous monomer solution is dispersed in the organic solvent in the presence of the surfactant or emulsifying agent. Upon removal of the organic solvent and further chemical and physical crosslinking of the droplets, nanogels are formed. The size of nanogels synthesized using this method can vary greatly depending on the type of surfactant and reaction medium used. Purifying nanogels produced using an emulsifying agent may also pose a challenge.

Microtemplate Polymerization

The addition of a monomer precursor solution and crosslinking agent to a microtemplate, or mold-type device, can initiate polymerization and the formation of nanogels. This method can be used to create nanogels in specific shapes and load them with various small molecules. Lithographic microtemplate polymerization is a similar process that uses a photoinitiator and light to trigger the formation of nanogels. Lithographic microtemplate polymerization can produce smaller nanogels on a length scale of <200 nm, which has a higher resolution compared to microtemplate polymerization that does not require a photoinitiator.

Cross-linking Micelles

Polymer-based micelles that undergo crosslinking reactions can induce the formation of nanogels. Crosslinking either the core or the shell of a preexisting micelles can synthesize nanogels with a “high degree of spatial organization”.

Composition and Structure

Materials

Six different types of nanogels. Created with BioRender.

Since biodegradability is an important characteristic of nanogels, these hydrogels are typically composed of natural or degradable synthetic polymers. Polysaccharides and proteins largely dominate the natural forms of polymers used to synthesize nanogels. Advantages of natural polymer-based nanogels include biocompatibility and degradability by cellular mechanisms in vivo. Natural polymers also tend to be nontoxic and bioactive in which they are more likely to induce biological cues that govern various aspects of cellular behavior.  However, natural-based polymers can still cause an immune response and possess other disadvantages such as variable degradation rates and heterogeneous structures. Conversely, synthetic-based polymers have more defined structures, increased stability, and controlled degradation rates. In comparison to natural-based polymers, synthetic polymers lack biological cues that may be necessary for specific therapeutic applications. Given that natural and synthetic polymers are defined by their own set of advantages and disadvantages, an ongoing area of research aims to create composite hydrogels for nanogel synthesis that combines synthetic and natural polymers to leverage the benefits of both in one nanogel formulation. 

Various types of natural and synthetic biomaterials used to synthesize nanogels.

Structure

The structure of a nanogel is dependent upon the synthesis mechanism and its application. Simple or traditional nanogels are nanoparticle-sized crosslinked polymer networks that swell in water. Hollow nanogels consisting only of an outer shell can increase the amount of cargo loaded into the platform. In other nanogel structures, the inner core and outer shell can be made of two different materials, such as a hydrophobic inner core to surround drugs or other small molecules and a hydrophilic outer shell that interacts with the external environment. The addition of a second linear monomer crosslinked to a nanogel is deemed a “hairy nanogel”. Different nanogel synthesis methods can be completed in sequential order to create multilayered nanogels, such as starting with ionotropic gelation and then combining anionic and cationic polymers in an aqueous solution. Functionalized nanogels, in which targeting ligands or stimuli-sensitive functional groups are conjugated to the outer shell of a nanogel, are also important for certain nanogel applications.

Stimuli-responsive Nanogels

Nanogels can be designed to respond to various stimuli including changes in pH and temperature or the presence of redox and light cues. Thoughtfully designed stimuli-responsive nanogels can be leveraged to transport and release different types of cargo to specific tissues within the body with increasing spatiotemporal resolution.

Stimuli-responsive nanogels with different examples of stimuli and two potential release mechanisms. Created with BioRender.

pH-responsive Nanogels

pH responsive nanogels are an attractive form of nanogel technology due to the different pH levels found within the body. Healthy tissues exhibit a pH of 7.4 whereas tumors can be as low as 6.5 and the stomach as low as 1.0. The protonation or deprotonation of certain functional groups can change the swelling rate and stability of a nanogel, thus resulting in the release of encapsulated cargo when exposed to different pH ranges. For example, anionic nanogels with carboxylic acid groups will collapse upon exposure to a pH that is smaller than the pKa of the nanogel polymer. Similarly, cationic nanogels with terminal amino groups will become protonated if the pH of the environment is less than the pKa of the hydrogel. In this case, the swelling rate of the nanogel will change and it will become more hydrophilic. Other groups have also previously cross-linked pH-responsive hydrazone linkages to polysaccharide-based nanogels that released a payload in an acidic environment.

Temperature-responsive Nanogels

The usage of thermoresponsive polymers in nanogel synthesis allows these systems to respond to changes in temperature. Depending on the chemical groups present, thermoresponsive polymers can either respond to a decrease in temperature or an increase in temperature. Both hydrophobic and hydrophilic groups are typically present in thermoresponsive polymer nanogels that react to temperature decreases, whereas nanogels that respond to temperature increases often have to be prepared by a hydrogen-bonded layering technique. Temperature-responsive nanogels are a potential strategy when a therapeutic is targeting the skin, which has a natural temperature gradient, or a region experiencing inflammation.

Redox-responsive Nanogels

Redox-responsive nanogels generally contain crosslinks formed by disulfide bonds or specific crosslinking agents such as cystamine. Nanogels made of bioreducible and bifunctional monomers have also been responsive to redox cues6. In the presence of redox agents such as thioredoxin and peroxiredoxin, these nanogels respond by releasing their cargo. Given that these two redox agents and several others are found in larger concentrations inside cells compared to their external environment, redox-responsive nanogels are a promising strategy for targeted intracellular delivery.

Light-responsive Nanogels

Light-responsive nanogels can be triggered to release their cargo with exposure to light at a certain wavelength. These nanogels are synthesized to contain specific acrylic or coumarin-based bonds that cleave during a photoreaction. With the tunability of the wavelength of light, energy, and time of irradiation, light-responsive nanogels can be triggered to degrade with an increased control over crosslinking density. For example, both the swelling and size of light-responsive nanogels with vinyl groups were found to decrease and produce a sustained release of drugs after irradiation with UV light.

Physiological Responses to Nanogels

Example of an endocytosis process for a drug-loaded nanogel. Created with BioRender.

Biocompatibility, Biodegradability, and Biodistribution

One major concern with any form of drug delivery system, including nanogels, is potential side effects and damage to healthy tissue in addition to causing a negative immune response with the introduction of a foreign substance. This has to be balanced with the need for nanogels to remain within circulation for an adequate period to deliver cargo and produce a therapeutic effect. To combat a significant immune response, degradable nanogels are the typical default since they are considered less toxic compared to non degradable nanogels. The compliance and small size of degradable nanogels also allows them to travel through blood vessels and reach their target area before consumption by immune cells or filtration by the liver and spleen.

Cellular Uptake Mechanisms

After nanogels exit the vasculature, they diffuse through the interstitial space into their target tissue. At the cellular level, nanogels can be internalized by a large number of different types of endocytosis that depend on the particle’s size, shape, and surface properties. Endocytosis is the most common mechanism that starts with the nanogels engulfed by the cellular membrane. The nanogels are transported in intracellular vesicles for delivery to endosomes that eventually combine with lysosomes. Once lysosomes are released into the cytosol of a cell, they deliver their cargo immediately or move to the appropriate cellular compartment.

Applications

Potential applications of nanogels include drug delivery agents, contrast agents for medical imaging or ¹⁹F MRI tracers, nanoactuators, and sensors.

Drug Delivery

Cancer Therapeutics

In 2022, over 1.9 million new cancer cases are projected in the U.S. alone. Nanogels are an attractive drug delivery solution for increasing both the efficacy of cancer therapeutics and their localization to cancer cells. Nanogels are currently being investigated for the treatment of different types of cancer, of which a few examples are listed here.

In one study, chitosan-based nanogels loaded with doxorubicin, a chemotherapeutic, with a positive surface charge demonstrated a lower colorectal cancer cell viability compared to control groups and a similarly loaded nanogel with a negative surface charge. Another group conjugated folic acid to nanogels loaded with cisplatin or doxorubicin and delivered these therapeutics to ovarian cancer cells, which overexpress the folate receptor that binds with folic acid. These conjugated nanogels produced a significant decrease in tumor growth in a mouse model compared to vehicle controls and showed a site-specific delivery model for nanogels that may be effective for other types of cancer with upregulated folate receptors. Interestingly, gelatin-based nanogels loaded with cisplatin and conjugated to epidermal growth factor receptor (EGFR) ligands have been reported to successfully target lung cancer cells both in vitro and in vivo, with additional work confirming the effectiveness of these nanogels when transformed into aerosol particles.

Example of using a therapeutic nanoparticle for targeted drug delivery to cancer cells. Created with BioRender.

Nucleic Acid-based Molecules

Nanogels are advantageous carriers of small, nucleic-acid based molecules that can be employed to treat a variety of diseases. Examples of three different types of molecules that fall into this category, oligonucleotides, miRNA, and nucleoside analogs, are discussed here.

In one study, cationic synthetic nanogels modified with insulin and transferrin were synthesized to transport oligonucleotides, a possible therapeutic and diagnostic tool for neurodegenerative disorders, to the brain. These nanogels successfully localized through an in vitro model of the blood-brain barrier and accumulated in the brain in a mouse model. With the treatment of cardiovascular diseases in mind, polysaccharide-based nanogels have been functionalized with fucoidan to target overexpressed P-selectin receptors on platelets and endothelial cells. After loading with miRNA, these nanogels bound to platelets and became internalized by an endothelial cell line. Nanogels have also been used to encapsulate phosphorylated nucleoside analogs, or active forms of anticancer therapeutics. In one study, nanogels loaded with nucleoside 5’-triphosphates underwent surface modifications and successfully bound to overexpressed folate receptors on breast cancer cells. These nanogels were then internalized by the cells and produced a significant increase in cytotoxicity compared to control groups.

Stimuli-responsive Nanogels for Drug Delivery

Nanogels that respond to various stimuli including changes in pH and temperature or the presence of redox and light cues have proven to be useful tools for drug delivery. One such responsive nanogel was designed to switch from a surface negative charge to a surface positive charge upon exposure to decrease in pH once inside a tumor. When loaded with a  chemotherapeutic agent, this technology induced a lower viability in 3D tumor spheroids compared to control groups. Another type of nanogel loaded with osteoarthritis anti-inflammatory drugs was found to significantly increase the amount of drug transported after topical application to the skin and exposure to its natural elevated temperature. One group reported a method to control the release rate of an antiplatelet medication from a nanogel by using UV light to alter the crosslinking density of the polymer and subsequently change the swelling rate. Additionally, other nanogels have been synthesized to include disulfide cleavable polymers that respond to reductive cues in the surrounding environment. One such nanogel was loaded with a chemotherapeutic agent and demonstrated a decrease in cell viability compared to a free version of the same agent.

Imaging and Diagnostics

In addition to drug delivery applications, nanogels have been utilized as a type of imaging modality as they can encapsulate small dyes and other reporter molecules.

An example of pH-responsive nanogels to increase MRI sensitivity. Created with BioRender.

MRI Imaging

Typical MRI contrast agents that contain gadolinium and manganese are quickly excreted from the body and carry risks of increased toxicity. Nanogels aim to circumvent these limitations by encapsulating these agents and increasing their relaxivity, or sensitivity. One study encapsulated gadolinium-III within a nanogel and observed a significant enhancement in relaxivity compared to a clinically available formulation of gadolinium-III. Another group developed pH-responsive nanogels containing both manganese oxide and superparamagnetic iron oxide nanoparticles that successfully imaged small tumors, where the pH was more acidic compared to the surrounding healthy tissues. Fluorine-containing nanogels can also be used as tracers for ¹⁹F MRI, because their aggregation and tissue binding has only minor effect on their ¹⁹F MRI signal. Furthermore, they can carry drugs and their physico-chemical properties of the polymers can be highly modulated.

PET Imaging

Similar to MRI imaging, metal radionuclides can be loaded into nanogels and crosslinked to obtain PET radiotracers for imaging. Nanogels containing copper isotopes commonly used for PET imaging demonstrated overall stability and accumulation in tumors, which produced  a higher signal in comparison to nearby tissue. Other studies have explored similar technologies with redox-responsive nanogels loaded with an isotope of gallium and other trivalent metals for PET imaging. Nanogels composed of dextran have also been developed for imaging tumor-associated macrophages with radionuclides and targeting the bone.

Other Optical Imaging

For in vivo fluorescence-based optical imaging, dyes that emit NIR wavelengths >700 nm are most effective, such as indocyanine green, but encounter limitations with reduced circulation time and nonspecific interactions with other biological factors that affect the fluorescence. pH-sensitive nanogels with functionalized surface receptors to target cancer cells were loaded with a fluorescent dye that was only released upon endocytosis. These nanogels successfully generated a fluorescent signal from within the cancer cells and many other groups have developed similar technologies.

Regenerative Medicine

Various applications of nanogels in regenerative medicine contexts including as injectable delivery vehicles and as components of  implantable polymeric scaffolds. Created with BioRender.

Wound Healing

Nanogels are a promising technology being explored to aid in the wound healing process. Given their ability to encapsulate various types of cargo, nanogels can strategically deliver anti-inflammatory agents, antimicrobial drugs, and necessary growth factors to facilitate new tissue growth and blood vessel formation. Chitosan-based nanogels have demonstrated an improved wound healing effect in previous studies. Chitosan-based nanogels encapsulating interleukin-2 were successfully used to stimulate the immune system and advance the wound healing process. Additionally, chitosan-based nanogels carrying an antibiotic, silver sulfadiazine, were found to decrease the size of second-degree burns in one in vivo study. In another study, silver-loaded nanogels were synthesized in a natural polymer-based solution containing aloe vera, and the presence of aloe vera led to increased healing and a decrease in wound size. With the goal of preventing infection and accelerating the healing process, one group has also published a new nanogel design consisting of an encapsulating core and a functionalized outer surface capable of targeting bacteria present in wounds.

Tissue Regeneration

To repair and regenerate damaged tissue, nanogels have been explored to not only encapsulate drugs and growth factors for local administration, but also to serve as porous scaffolds at a tissue implantation site. Boron-containing temperature-responsive nanogels formed a solid scaffold upon injection into a critical bone defect and continued to induce the production of new osteoblast cells. To treat the effects of myocardial infarction, one in vivo study loaded temperature-responsive nanogels with cardiac stem cells and observed improved cardiac function through an increase in left ventricular ejection. Blood vessels have been successfully regenerated in an in vivo model of ischemia using nanogels to encapsulate vascular endothelial growth factors. Heparin-based nanogels loaded with growth factors have also been tested in the regeneration of the urethral muscle that causes urinary incontinence.

Other Applications

Sensors

A fluorescent nanogel thermometer was developed to measure temperatures to within 0.5 °C (0.90 °F) in living cells. The cell absorbs water when colder and squeezes the water out as its internal temperature rises; the relative quantity of water masks or exposes the fluorescence of the nanogel.

Resurrection

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Resurrection 

Plaque depicting saints rising from the dead

Resurrection or anastasis is the concept of coming back to life after death. In a number of religions, a dying-and-rising god is a deity which dies and is resurrected. Reincarnation is a similar process hypothesized by other religions, which involves the same person or deity coming back to live in a different body, rather than the same one.

The resurrection of the dead is a standard eschatological belief in the Abrahamic religions. As a religious concept, it is used in two distinct respects: a belief in the resurrection of individual souls that is current and ongoing (Christian idealism, realized eschatology), or else a belief in a singular resurrection of the dead at the end of the world. Some believe the soul is the actual vehicle by which people are resurrected.

The death and resurrection of Jesus is a central focus of Christianity. Christian theological debate ensues with regard to what kind of resurrection is factual – either a spiritual resurrection with a spirit body into Heaven, or a material resurrection with a restored human body. While most Christians believe Jesus' resurrection from the dead and ascension to Heaven was in a material body, some believe it was spiritual.

Like the Abrahamic religions, Hinduism also has a core belief in resurrection and reincarnation. This is known as saṃsāra.

Etymology

Resurrection, from the Latin noun resurrectio -onis, from the verb rego, "to make straight, rule" + preposition sub, "under", altered to subrigo and contracted to surgo, surrexi, surrectum ("to rise", "get up", "stand up") + preposition re-, "again", thus literally "a straightening from under again".

Religion

Ancient religions in the Near East

See also: Dying-and-rising god

The concept of resurrection is found in the writings of some ancient non-Abrahamic religions in the Middle East. A few extant Egyptian and Canaanite writings allude to dying and rising gods such as Osiris and Baal. Sir James Frazer in his book The Golden Bough relates to these dying and rising gods, but many of his examples, according to various scholars, distort the sources. Taking a more positive position, Tryggve Mettinger argues in his recent book that the category of rise and return to life is significant for Ugaritic Baal, Melqart, Adonis, Eshmun, Osiris and Dumuzi.

Ancient Greek religion

In ancient Greek religion a number of men and women became physically immortal as they were resurrected from the dead. Asclepius was killed by Zeus, only to be resurrected and transformed into a major deity. Achilles, after being killed, was snatched from his funeral pyre by his divine mother Thetis and resurrected, brought to an immortal existence in either Leuce, the Elysian plains or the Islands of the Blessed. Memnon, who was killed by Achilles, seems to have received a similar fate. Alcmene, Castor, Heracles, and Melicertes, were also among the figures sometimes considered to have been resurrected to physical immortality. According to Herodotus's Histories, the seventh century BC sage Aristeas of Proconnesus was first found dead, after which his body disappeared from a locked room. Later he found not only to have been resurrected but to have gained immortality.

Many other figures, like a great part of those who fought in the Trojan and Theban wars, Menelaus, and the historical pugilist Cleomedes of Astupalaea, were also believed to have been made physically immortal, but without having died in the first place. Indeed, in Greek religion, immortality originally always included an eternal union of body and soul. As may be witnessed even into the Christian era, not least by the complaints of various philosophers over popular beliefs, traditional Greek believers maintained the conviction that certain individuals were resurrected from the dead and made physically immortal and that for the rest of us, we could only look forward to an existence as disembodied and dead souls.

Greek philosophers generally denied this traditional religious belief in physical immortality. Writing his Lives of Illustrious Men (Parallel Lives) in the first century, the Middle Platonic philosopher Plutarch in his chapter on Romulus gave an account of the mysterious disappearance and subsequent deification of this first king of Rome, comparing it to traditional Greek beliefs such as the resurrection and physical immortalization of Alcmene and Aristeas the Proconnesian, "for they say Aristeas died in a fuller's work-shop, and his friends coming to look for him, found his body vanished; and that some presently after, coming from abroad, said they met him traveling towards Croton". Plutarch openly scorned such beliefs held in traditional ancient Greek religion, writing, "many such improbabilities do your fabulous writers relate, deifying creatures naturally mortal."

Alcestis undergoes resurrection over a three-day period of time, but without achieving immortality.

The parallel between these traditional beliefs and the later resurrection of Jesus was not lost on the early Christians, as Justin Martyr argued: "when we say ... Jesus Christ, our teacher, was crucified and died, and rose again, and ascended into heaven, we propose nothing different from what you believe regarding those whom you consider sons of Zeus." (1 Apol. 21).

Buddhism

Further information: Rebirth (Buddhism)

There are stories in Buddhism where the power of resurrection was allegedly demonstrated in Chan or Zen tradition. One is the legend of Bodhidharma, the Indian master who brought the Ekayana school of India that subsequently became Chan Buddhism to China.

The other is the passing of Chinese Chan master Puhua (Japanese:Jinshu Fuke) and is recounted in the Record of Linji (Japanese: Rinzai Gigen). Puhua was known for his unusual behavior and teaching style so it is no wonder that he is associated with an event that breaks the usual prohibition on displaying such powers. Here is the account from Irmgard Schloegl's "The Zen Teaching of Rinzai".

"One day at the street market Fuke was begging all and sundry to give him a robe. Everybody offered him one, but he did not want any of them. The master [Linji] made the superior buy a coffin, and when Fuke returned, said to him: "There, I had this robe made for you." Fuke shouldered the coffin, and went back to the street market, calling loudly: "Rinzai had this robe made for me! I am off to the East Gate to enter transformation" (to die)." The people of the market crowded after him, eager to look. Fuke said: "No, not today. Tomorrow, I shall go to the South Gate to enter transformation." And so for three days. Nobody believed it any longer. On the fourth day, and now without any spectators, Fuke went alone outside the city walls, and laid himself into the coffin. He asked a traveler who chanced by to nail down the lid.

The news spread at once, and the people of the market rushed there. On opening the coffin, they found that the body had vanished, but from high up in the sky they heard the ring of his hand bell."

Christianity

In Christianity, resurrection most critically concerns the resurrection of Jesus, but also includes the resurrection of Judgment Day known as the resurrection of the dead by those Christians who subscribe to the Nicene Creed (which is the majority or mainstream Christianity), as well as the resurrection miracles done by Jesus and the prophets of the Old Testament.

Resurrection miracles

The Resurrection of Lazarus, painting by Leon Bonnat, France, 1857.

 

Main article: Miracles of Jesus § Resurrection of the dead

In the New Testament, Jesus is said to have raised several persons from death. These resurrections included the daughter of Jairus shortly after death, a young man in the midst of his own funeral procession, and Lazarus of Bethany, who had been buried for four days.

During the Ministry of Jesus on earth, before his death, Jesus commissioned his Twelve Apostles to, among other things, raise the dead.

Similar resurrections are credited to the apostles and Catholic saints. In the Acts of the Apostles, Saint Peter raised a woman named Dorcas (also called Tabitha), and Paul the Apostle revived a man named Eutychus who had fallen asleep and fell from a window to his death. According to the Gospel of Matthew, after Jesus's resurrection, many of those previously dead came out of their tombs and entered Jerusalem, where they appeared to many. Following the Apostolic Age, many saints were said to resurrect the dead, as recorded in Orthodox Christian hagiographies. St Columba supposedly raised a boy from the dead in the land of Picts.

Resurrection of Jesus

Main articles: Life-death-rebirth deity, Resurrection of Jesus, Easter, and Resurrection appearances of Jesus

 

Resurrection of Jesus

Christians regard the resurrection of Jesus as the central doctrine in Christianity. Others take the incarnation of Jesus to be more central; however, it is the miracles – and particularly his resurrection – which provide validation of his incarnation. According to Paul, the entire Christian faith hinges upon the centrality of the resurrection of Jesus and the hope for a life after death. The Apostle Paul wrote in his first letter to the Corinthians:

If only for this life we have hope in Christ, we are to be pitied more than all men. But Christ has indeed been raised from the dead, the first fruits of those who have fallen asleep.

Resurrection of the dead

Main articles: Universal resurrection § Christianity, and Christian eschatology § Resurrection of the dead

Christianity started as a religious movement within 1st-century Judaism (late Second Temple Judaism), and it retains what the New Testament itself claims was the Pharisaic belief in the afterlife and resurrection of the dead. Whereas this belief was only one of many beliefs held about the world to come in Second Temple Judaism, and was notably rejected by the Sadducees, but accepted by the Pharisees (cf. Acts 23:6-8). Belief in the resurrection became dominant within Early Christianity and already in the Gospels of Luke and John, included an insistence on the resurrection of the flesh. Most modern Christian churches continue to uphold the belief that there will be a final resurrection of the dead and world to come.

Belief in the resurrection of the dead, and Jesus' role as judge, is codified in the Apostles' Creed, which is the fundamental creed of Christian baptismal faith. The Book of Revelation also makes many references about the Day of Judgment when the dead will be raised.

The emphasis on the literal resurrection of the flesh remained strong in the medieval ages, and still remains so in Orthodox churches. In modern Western Christianity, especially "from the 17th to the 19th century, the language of popular piety no longer evoked the resurrection of the soul but everlasting life. Although theological textbooks still mentioned resurrection, they dealt with it as a speculative question more than as an existential problem."

Difference from Platonic philosophy

In Platonic philosophy and other Greek philosophical thought, at death the soul was said to leave the inferior body behind. The idea that Jesus was resurrected spiritually rather than physically even gained popularity among some Christian teachers, whom the author of 1 John declared to be antichrists. Similar beliefs appeared in the early church as Gnosticism. However, in Luke 24:39, the resurrected Jesus expressly states "behold my hands and my feet, that it is I myself. Handle me and see, for a spirit does not have flesh and bones as you see, I have."

Hinduism

Further information: Reincarnation

There are folklore, stories, and extractions from certain holy texts that refer to resurrections. One major folklore is that of Savitri saving her husband's life from Yamraj. In the Ramayana, after Ravana was slain by Rama in a great battle between good and evil, Rama requests the king of Devas, Indra, to restore the lives of all the monkeys who died in the great battle. Mahavatar Babaji and Lahiri Mahasaya are also believed to have resurrected themselves.

Islam

Main article: Islamic eschatology

Belief in the Day of Resurrection (yawm al-qiyāmah) is also crucial for Muslims. They believe the time of Qiyāmah is preordained by God but unknown to man. The trials and tribulations preceding and during the Qiyāmah are described in the Quran and the hadith, and also in the commentaries of scholars. The Quran emphasizes bodily resurrection, a break from the pre-Islamic Arabian understanding of death.

According to Nasir Khusraw (d. after 1070), an Ismaili thinker of the Fatimid era, the Resurrection (Qiyāma) will be ushered by the Lord of the Resurrection (Qāʾim al-Qiyāma), an individual symbolizing the purpose and pinnacle of creation from among the progeny of Muhammad and his Imams. Through this individual, the world will come out of darkness and ignorance and “into the light of her Lord” (Quran 39:69). His era, unlike that of the enunciators of the divine revelation (nāṭiqs) before him, is not one where God prescribes the people to work but instead one where God rewards them. Preceding the Lord of the Resurrection (Qāʾim) is his proof (ḥujjat). The Qur’anic verse stating that “the night of power (laylat al-qadr) is better than a thousand months” (Quran 97:3) is said to refer to this proof, whose knowledge is superior to that of a thousand Imams, though their rank, collectively, is one. Hakim Nasir also recognizes the successors of the Lord of the Resurrection to be his deputies (khulafāʾ).

Judaism

Main article: Jewish eschatology

There are three explicit examples in the Hebrew Bible of people being resurrected from the dead:

• The prophet Elijah prays and God raises a young boy from death (1 Kings 17:17-24)
• Elisha raises the son of the Woman of Shunem (2 Kings 4:32-37) whose birth he previously foretold (2 Kings 4:8-16)
• A dead man's body that was thrown into the dead Elisha's tomb is resurrected when the body touches Elisha's bones (2 Kings 13:21)

According to Herbert C. Brichto, writing in Reform Judaism's Hebrew Union College Annual, the family tomb is the central concept in understanding biblical views of the afterlife. Brichto states that it is "not mere sentimental respect for the physical remains that is...the motivation for the practice, but rather an assumed connection between proper sepulture and the condition of happiness of the deceased in the afterlife".

According to Brichto, the early Israelites apparently believed that the graves of family, or tribe, united into one, and that this unified collectivity is to what the Biblical Hebrew term Sheol refers, the common grave of humans. Although not well defined in the Tanakh, Sheol in this view was a subterranean underworld where the souls of the dead went after the body died. The Babylonians had a similar underworld called Aralu, and the ancient Greeks had one known as Hades. According to Brichto, other biblical names for Sheol were Abaddon "ruin", found in Psalm 88:11, Job 28:22 and Proverbs 15:11; Bor "pit", found in Isaiah 14:15, 24:22, Ezekiel 26:20; and Shakhat "corruption", found in Isaiah 38:17, Ezekiel 28:8.

During the Second Temple period, there developed a diversity of beliefs concerning the resurrection. The concept of resurrection of the physical body is found in 2 Maccabees, according to which it will happen through re-creation of the flesh. Resurrection of the dead also appears in detail in the extra-canonical Book of Enoch, 2 Baruch, and 2 Esdras. According to the British scholar in ancient Judaism Philip R. Davies, there is “little or no clear reference … either to immortality or to resurrection from the dead” in the texts of the Dead Sea Scrolls. C.D. Elledge, however, argues that some form of resurrection may be referred to in the Dead Sea texts 4Q521, Pseudo-Ezekiel, and 4QInstruction.

Both Josephus and the New Testament record that the Sadducees did not believe in an afterlife, but the sources vary on the beliefs of the Pharisees. The New Testament claims that the Pharisees believed in the resurrection, but does not specify whether this included the flesh or not. According to Josephus, who himself was a Pharisee, the Pharisees held that only the soul was immortal and the souls of good people will “pass into other bodies,” while “the souls of the wicked will suffer eternal punishment.” Paul the Apostle, who also was a Pharisee, said that at the resurrection what is "sown as a natural body is raised a spiritual body." The Book of Jubilees seems to refer to the resurrection of the soul only, or to a more general idea of an immortal soul.

Anastasis in contemporary philosophy

Anastasis or Ana-stasis is a concept in contemporary philosophy emerging from the works of Jean-Luc Nancy, Divya Dwivedi and Shaj Mohan. Nancy developed the concept through his interpretation of paintings depicting the resurrection of Jesus Christ. Dwivedi and Mohan, referring to Nancy, defined Ana-stasis as coming over stasis, which is a method for philosophy to overcome its end as Martin Heidegger defined. This concept is noted to be linked in the works of Nancy, Dwivedi and Mohan to have a relation to Heidegger's “other beginning of philosophy”. The use of the phrase “anastasis of philosophy” indicates such other beginning.

Technological resurrection

Cryonics is the low-temperature freezing (usually at −196 °C or −320.8 °F or 77.1 K) of a human corpse or severed head, with the speculative hope that resurrection may be possible in the future. Cryonics is regarded with skepticism within the mainstream scientic community. It is generally viewed as a pseudoscience, and has been characterized as quackery.

Russian cosmist Nikolai Fyodorovich Fyodorov advocated resurrection of the dead using scientific methods. Fedorov tried to plan specific actions for scientific research of the possibility of restoring life and making it infinite. His first project is connected with collecting and synthesizing decayed remains of dead based on "knowledge and control over all atoms and molecules of the world". The second method described by Fedorov is genetic-hereditary. The revival could be done successively in the ancestral line: sons and daughters restore their fathers and mothers, they in turn restore their parents and so on. This means restoring the ancestors using the hereditary information that they passed on to their children. Using this genetic method it is only possible to create a genetic twin of the dead person. It is necessary to give back the revived person his old mind, his personality. Fedorov speculates about the idea of "radial images" that may contain the personalities of the people and survive after death. Nevertheless, Fedorov noted that even if a soul is destroyed after death, Man will learn to restore it whole by mastering the forces of decay and fragmentation.

In his 1994 book The Physics of Immortality, American physicist Frank J. Tipler, an expert on the general theory of relativity, presented his Omega Point Theory which outlines how a resurrection of the dead could take place at the end of the cosmos. He posits that humans will evolve into robots which will turn the entire cosmos into a supercomputer which will, shortly before the Big Crunch, perform the resurrection within its cyberspace, reconstructing formerly dead humans (from information captured by the supercomputer from the past light cone of the cosmos) as avatars within its metaverse.

David Deutsch, British physicist and pioneer in the field of quantum computing, formerly agreed with Tipler's Omega Point cosmology and the idea of resurrecting deceased people with the help of quantum computers but he is critical of Tipler's theological views.

Italian physicist and computer scientist Giulio Prisco presents the idea of "quantum archaeology", "reconstructing the life, thoughts, memories, and feelings of any person in the past, up to any desired level of detail, and thus resurrecting the original person via 'copying to the future'".

In his book Mind Children, roboticist Hans Moravec proposed that a future supercomputer might be able to resurrect long-dead minds from the information that still survived. For example, this information can be in the form of memories, filmstrips, medical records, and DNA.

Ray Kurzweil, American inventor and futurist, believes that when his concept of singularity comes to pass, it will be possible to resurrect the dead by digital recreation.

In their science fiction novel The Light of Other Days, Sir Arthur Clarke and Stephen Baxter imagine a future civilization resurrecting the dead of past ages by reaching into the past, through micro wormholes and with nanorobots, to download full snapshots of brain states and memories.

Both the Church of Perpetual Life and the Terasem Movement consider themselves transreligions and advocate for the use of technology to indefinitely extend the human lifespan.

Zombies

Main article: Zombie

A zombie (Haitian French: zombi, Haitian Creole: zonbi) is a fictional undead being created through the reanimation of a human corpse. Zombies are most commonly found in horror and fantasy genre works. The term comes from Haitian folklore, where a zombie is a dead body reanimated through various methods, most commonly magic.

Disappearances (as distinct from resurrection)

See also: Entering heaven alive

As knowledge of different religions has grown, so have claims of bodily disappearance of some religious and mythological figures. In ancient Greek religion, this was a way the gods made some physically immortal, including such figures as Cleitus, Ganymede, Menelaus, and Tithonus. After his death, Cycnus was changed into a swan and vanished. In his chapter on Romulus from Parallel Lives, Plutarch criticises the continuous belief in such disappearances, referring to the allegedly miraculous disappearance of the historical figures Romulus, Cleomedes of Astypalaea, and Croesus. In ancient times, Greek and Roman pagan similarities were explained by the early Christian writers, such as Justin Martyr, as the work of demons, with the intention of leading Christians astray.

In the Buddhist Epic of King Gesar, also spelled as Geser or Kesar, at the end, chants on a mountain top and his clothes fall empty to the ground. The body of the first Guru of the Sikhs, Guru Nanak Dev, is said to have disappeared and flowers left in place of his dead body.

Lord Raglan's Hero Pattern lists many religious figures whose bodies disappear, or have more than one sepulchre. B. Traven, author of The Treasure of the Sierra Madre, wrote that the Inca Virococha arrived at Cusco (in modern-day Peru) and the Pacific seacoast where he walked across the water and vanished. It has been thought that teachings regarding the purity and incorruptibility of the hero's human body are linked to this phenomenon. Perhaps, this is also to deter the practice of disturbing and collecting the hero's remains. They are safely protected if they have disappeared.

The first such case mentioned in the Bible is that of Enoch (son of Jared, great-grandfather of Noah, and father of Methuselah). Enoch is said to have lived a life where he "walked with God", after which "he was not, for God took him" (Genesis 5:1–18). In Deuteronomy (34:6) Moses is secretly buried. Elijah vanishes in a whirlwind 2 Kings (2:11). In the Synoptic Gospels, after hundreds of years these two earlier Biblical heroes suddenly reappear, and are reportedly seen walking with Jesus, then again vanish.^[65] In the Gospel of Luke, the last time Jesus is seen (24:51) he leaves his disciples by ascending into the sky. This ascension of Jesus was a “disappearance” of sorts as recorded by Luke but was after the physical resurrection occurring several days before.

Supramolecular polymer

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Supramolecular_polymer 

The term "polymer" refers to large molecules whose structure is composed of multiple repeating units and the prefix "supra" meaning "beyond the limits of". Supramolecular polymers are a new category of polymers that can potentially be used for material applications beyond the limits of conventional polymers. By definition, supramolecular polymers are polymeric arrays of monomeric units that are connected by reversible and highly directional secondary interactions–that is, non-covalent bonds. These non-covalent interactions include van der Waals interactions, hydrogen bonding, Coulomb or ionic interactions, π-π stacking, metal coordination, halogen bonding, chalcogen bonding, and host–guest interaction. The direction and strength of the interactions are precisely tuned so that the array of molecules behaves as a polymer (that is, it behaves in a way that can be described by the theories of polymer physics) in dilute and concentrated solution, as well as in the bulk.

In conventional polymers, monomeric units are linked by strong covalent bonds and have excellent properties as materials; however, high temperatures and pressures are typically required for processing due to polymer entanglement in the highly viscous melt. Supramolecular polymers combine good material properties with low-viscosity melts that are easy to handle. Additionally, some supramolecular polymers have unique characteristics, such as the ability to self-heal fractures. Although covalent polymers can be recycled, their strong covalent bonds never disintegrate, and go on to negatively affect the environment as plastic wastes. Thus, supramolecular polymers are increasingly getting attention because of their potential for the design of responsive, adaptive, self-healing, and environmentally friendly materials.

History

Monomeric motifs and types of interactions used for the preparation of supramolecular polymers

Modern concept of polymers credited to Hermann Staudinger, who substantiated the existence of covalently linked ultralong molecules in 1920, which he called as macromolecules. The preamble of the field of supramolecular polymers can be considered dye-aggregates and host-guest complexes. In early 19thcentury, scientists working in the field of pigments have noticed certain dye aggregates that may formed via "a special kind of polymerization", however no theory was proposed. After the establishment of the field of supramolecular chemistry and after the award of the Nobel Prize in chemistry in 1987 to Donald J. Cram, Jean-Marie Lehn, and Charles J. Pedersen, chemists started to design and study larger assembled structures from small molecules. In 1988, Takuzo Aida, a Japanese polymer chemist, reported the concept of cofacial assembly wherein the amphiphilic porphyrin monomers are connected via van der Waals interaction forming one-dimensional architectures in solution, which can be considered as a prototype of supramolecular polymers. In the same year 1988, James D. Wuest introduced one-dimensional aggregates based on hydrogen bonding interaction in the crystalline state. With a different strategyusing hydrogen bonds, Jean M. J. Fréchet showed in 1989 that mesogenic molecules with carboxylic acid and pyridyl motifs, upon mixing in bulk, heterotropically dimerize to form a stable liquid crystalline structure. In 1990, Jean-Marie Lehn showed that this strategy can be expanded to form a new category of polymers, which he called "liquid crystalline supramolecular polymer" using complementary triple hydrogen bonding motifs in bulk. In 1993, M. Reza Ghadiri reported a nanotubular supramolecular polymer where a b-sheet-forming macrocyclic peptide monomer assembled together via multiple hydrogen bonding between adjacent macrocycles. In 1994, Anselm. C. Griffin showed an amorphous supramolecular material using a single hydrogen bond between a homotropic molecules having carboxylic acid and pyridine termini. The idea to make mechanically strong polymeric materials by 1D supramolecular association of small molecules requires a high association constant between the repeating building blocks. In 1997, E.W. "Bert" Meijer reported a telechelic monomer with ureidopyrimidinone termini as a "self-complementary" quadruple hydrogen bonding motif and demonstrated that the resulting supramolecular polymer in chloroform shows a temperature-dependent viscoelastic property in solution. This is the first demonstration that supramolecular polymers, when sufficiently mechanically robust, are physically entangled in solution.

Formation mechanisms

Monomers undergoing supramolecular polymerization are considered to be in equilibrium with the growing polymers, and thermodynamic factors therefore dominate the system. However, when the constituent monomers are connected via strong and multivalent interactions, a "metastable" kinetic state can dominate the polymerization. An externally supplied energy, in the form of heat in most cases, can transform the "metastable" state into a thermodynamically stable polymer. A clear understanding of multiple pathways exist in supramolecular polymerization is still under debate, however, the concept of "pathway complexity", introduced by E.W. "Bert" Meijer, shed a light on the kinetic behavior of supramolecular polymerization. Thereafter, many dedicated scientists are expanding the scope of "pathway complexity" because it can produce a variety of interesting assembled structures from the same monomeric units. Along this line of kinetically controlled processes, supramolecular polymers having "stimuli-responsive" and "thermally bisignate" characteristics is also possible.

In conventional covalent polymerization, two models based on step-growth and chain-growth mechanisms are operative. Nowadays, a similar subdivision is acceptable for supramolecular polymerization; isodesmic also known as equal-K model (step-growth mechanism) and cooperative or nucleation-elongation model (chain-growth mechanism). A third category is seeded supramolecular polymerization, which can be considered as a special case of chain-growth mechanism.

Step-growth polymerization

Schematics of "pathway-complexity" and "chain-growth" mechanisms operative in supramolecular polymerization

Supramolecular equivalent of step-growth mechanism is commonly known as isodesmic or equal-K model (K represents the total binding interaction between two neighboring monomers). In isodesmic supramolecular polymerization, no critical temperature or concentration of monomers is required for the polymerization to occur and the association constant between polymer and monomer is independent of the polymer chain length. Instead, the length of the supramolecular polymer chains rises as the concentration of monomers in the solution increases, or as the temperature decreases. In conventional polycondensation, the association constant is usually large that leads to a high degree of polymerization; however, a byproduct is observed. In isodesmic supramolecular polymerization, due to non-covalent bonding, the association between monomeric units is weak, and the degree of polymerization strongly depends on the strength of interaction, i.e. multivalent interaction between monomeric units. For instance, supramolecular polymers consisting of bifunctional monomers having single hydrogen bonding donor/acceptor at their termini usually end up with low degree of polymerization, however those with quadrupole hydrogen bonding, as in the case of ureidopyrimidinone motifs, result in a high degree of polymerization. In ureidopyrimidinone-based supramolecular polymer, the experimentally observed molecular weight at semi-dilute concentrations is in the order of 10⁶ Dalton and the molecular weight of the polymer can be controlled by adding mono-functional chain-cappers.

Chain-growth polymerization

Conventional chain-growth polymerization involves at least two phases; initiation and propagation, while and in some cases termination and chain transfer phases also occur. Chain-growth supramolecular polymerization in a broad sense involves two distinct phases; a less favored nucleation and a favored propagation. In this mechanism, after the formation of a nucleus of a certain size, the association constant is increased, and further monomer addition becomes more favored, at which point the polymer growth is initiated. Long polymer chains will form only above a minimum concentration of monomer and below a certain temperature. However, to realize a covalent analogue of chain-growth supramolecular polymerization, a challenging prerequisite is the design of appropriate monomers that can polymerize only by the action of initiators. Recently one example of chain-growth supramolecular polymerization with "living" characteristics is demonstrated. In this case, a bowl-shaped monomer with amide-appended side chains form a kinetically favored intramolecular hydrogen bonding network and does not spontaneously undergo supramolecular polymerization at ambient temperatures. However, an N-methylated version of the monomer serves as an initiator by opening the intramolecular hydrogen bonding network for the supramolecular polymerization, just like ring-opening covalent polymerization. The chain end in this case remains active for further extension of supramolecular polymer and hence chain-growth mechanism allows for the precise control of supramolecular polymer materials.

Seeded polymerization

This is a special category of chain-growth supramolecular polymerization, where the monomer nucleates only in an early stage of polymerization to generate "seeds" and becomes active for polymer chain elongation upon further addition of a new batch of monomer. A secondary nucleation is suppressed in most of the case and thus possible to realize a narrow polydispersity of the resulting supramolecular polymer. In 2007, Ian Manners and Mitchell A. Winnik introduced this concept using a polyferrocenyldimethylsilane–polyisoprene diblock copolymer as the monomer, which assembles into cylindrical micelles. When a fresh feed of the monomer is added to the micellar "seeds" obtained by sonication, the polymerization starts in a living polymerization manner. They named this method as crystallization-driven self-assembly (CDSA) and is applicable to construct micron-scale supramolecular anisotropic structures in 1D–3D. A conceptually different seeded supramolecular polymerization was shown by Kazunori Sugiyasu in a porphyrin-based monomer bearing amide-appended long alkyl chains. At low temperature, this monomer preferentially forms spherical J-aggregates while fibrous H-aggregates at higher temperature. By adding a sonicated mixture of the J-aggregates ("seeds") into a concentrated solution of the J-aggregate particles, long fibers can be prepared via living seeded supramolecular polymerization. Frank Würthner achieved similar seeded supramolecular polymerization of amide functionalized perylene bisimide as monomer. Importantly, the seeded supramolecular polymerization is also applicable to prepare supramolecular block copolymers.

Examples

Hydrogen bonding interaction

Monomers capable of forming single, double, triple or quadruple hydrogen bonding has been utilized for making supramolecular polymers, and increased association of monomers obviously possible when monomers have maximum number of hydrogen bonding donor/acceptor motifs. For instance, ureidopyrimidinone-based monomer with self-complementary quadruple hydrogen bonding termini polymerized in solution, accordingly with the theory of conventional polymers and displayed a distinct viscoelastic nature at ambient temperatures.

π-π stacking

Monomers with aromatic motifs such as bis(merocyanine), oligo(para-phenylenevinylene) (OPV), perylene bisimide (PBI) dye, cyanine dye, corannulene and nano-graphene derivatives have been employed to prepare supramolecular polymers. In some cases, hydrogen bonding side chains appended onto the core aromatic motif help to hold the monomer strongly in the supramolecular polymer. A notable system in this category is a nanotubular supramolecular polymer formed by the supramolecular polymerization of amphiphilic hexa-peri-hexabenzocoronene (HBC) derivatives. Generally, nanotubes are categorized as 1D objects morphologically, however, their walls adopt a 2D geometry and therefore require a different design strategy. HBC amphiphiles in polar solvents solvophobically assemble into a 2D bilayer membrane, which roles up into a helical tape or a nanotubular polymer. Conceptually similar amphiphilic design based on cyanine dye and zinc chlorin dye also polymerize in water resulting in nanotubular supramolecular polymers.

Host-guest interaction

A variety of supramolecular polymers can be synthesized by using monomers with host-guest complementary binding motifs, such as crown ethers/ammonium ions, cucurbiturils/viologens, calixarene/viologens, cyclodextrins/adamantane derivatives, and pillar arene/imidazolium derivatives [30–33]. When the monomers are "heteroditopic", supramolecular copolymers results, provided the monomers does not homopolymerize. Akira Harada was one of the firstwhorecognize the importance of combining polymers and cyclodextrins. Feihe Huang showed an example of supramolecular alternating copolymer from two heteroditopic monomers carrying both crown ether and ammonium ion termini. Takeharo Haino demonstrated an extreme example of sequence control in supramolecular copolymer, where three heteroditopic monomers are arranged in an ABC sequence along the copolymer chain. The design strategy utilizing three distinct binding interactions; ball-and-socket (calix[5]arene/C60), donor-acceptor (bisporphyrin/trinitrofluorenone), and Hamilton's H-bonding interactions is the key to attain a high orthogonality to form an ABC supramolecular terpolymer.

Chirality

Stereochemical information of a chiral monomer can be expressed in a supramolecular polymer. Helical supramolecular polymer with P-and M-conformation are widely seen, especially those composed of disc-shaped monomers. When the monomers are achiral, both P-and M-helices are formed in equal amounts. When the monomers are chiral, typically due to the presence of one or more stereocenters in the side chains, the diastereomeric relationship between P- and M-helices leads to the preference of one conformation over the other. Typical example is a C₃-symmetric disk-shaped chiral monomer that forms helical supramolecular polymers via the "majority rule". A slight excess of one enantiomer of the chiral monomer resulted in a strong bias to either the right-handed or left-handed helical geometry at the supramolecular polymer level. In this case, a characteristic nonlinear dependence of the anisotropic factor, g, on the enantiomeric excess of a chiral monomer can be generally observed. Like in small molecule based chiral system, chirality of a supramolecular polymer also affected by chiral solvents. Some application such as a catalyst for asymmetric synthesis and circular polarized luminescence are observed in chiral supramolecular polymers too.

Copolymers

A copolymer is formed from more than one monomeric species. Advanced polymerization techniques have been established for the preparation of covalent copolymers, however supramolecular copolymers are still in its infancy and is slowly progressing. In recent years, all plausible category of supramolecular copolymers such as random, alternating, block, blocky, or periodic has been demonstrated in a broad sense.

Properties

In the last 30 years, the field of supramolecular polymers has grown into a very important new branch of polymer science. It has attracted numerous research activities in academia and industrial laboratories worldwide. New dynamic materials with a variety of anomalous properties are added to the field of materials engineering. Many applications in sustainability (easy processing and recycling), electronics, and medicine as well as cosmetics have become available.

Reversibility and dynamicity

One of the important properties of supramolecular polymers is their reversible interactions in the monomeric array. When the interaction between monomers are sufficiently strong, interesting material properties can be expected. The thermodynamic stability of a supramolecular polymer can be described using the association constant, K_ass. When K_ass ≤ 10⁴M⁻¹, the polymeric aggregates are typically small in size and do not show any interesting properties and when K_ass≥ 10¹⁰ M⁻¹, the supramolecular polymer behaves just like covalent polymers due to the lack of dynamics. So, an optimum K_ass = 10⁴–10¹⁰M⁻¹need to be attained for producing functional supramolecular polymers. The dynamics and stability of the supramolecular polymers often affect by the influence of additives (e.g. co-solvent or chain-capper). When a good solvent, for instance chloroform, is added to a supramolecular polymer in a poor solvent, for instance heptane, the polymer disassembles. However, in some cases, cosolvents contribute the stabilization/destabilization of supramolecular polymer. For instance, supramolecular polymerization of a hydrogen bonding porphyrin-based monomer in a hydrocarbon solvent containing a minute amount of a hydrogen bond scavenging alcohol shows distinct pathways, i.e. polymerization favored both by cooling as well as heating, and is known as "thermally bisignate supramolecular polymerization". In another example, minute amounts of molecularly dissolved water molecules in apolar solvents, like methylcyclohexane, become part of the supramolecular polymer at lower temperatures, due to specific hydrogen bonding interaction between the monomer and water.

Self-healing

One of the fascinating properties of supramolecular polymers is its ability to self-heal upon fracture occur. A supramolecular rubber based on vitrimers, introduced by Ludwik Leibler, can self-heal simply by pressing the two broken edges of the material together. In this case, fractures occur when hydrogen bonds between monomers in the material are broken; bringing the edges of the fracture together allows the hydrogen bonds to re-form, sealing up the gap. Impressively, the dynamic behavior of the hydrogen bonds does not compromise the properties of the material. High mechanical strength of a material and self-healing ability is generally mutually exclusive. Thus, a glassy material that can self-heal at room temperature remained a challenge until recently. In an elegant design, Takuzo Aida introduced an innovative polymer glass composed of a supramolecularly polymerized oligomeric ether thiourea, which is mechanically robust (e= 1.4 GPa) but can self-heal, even at room temperature, just by a compression at the fractured surfaces. The invention of self-healable polymer glass updated the preconception that only soft rubbery materials can heal.

Examples of hydrogen-bonding based self-healing 'supramolecular rubber' (a) and 'polymer glass' (b).

Another strategy uses a bivalent poly(isobutylene)s (PIBs) with barbituric acid functionalized at head and tail. Multiple hydrogen bonding existed between the carbonyl group and amide group of barbituric acid enable it to form a supramolecular network. In this case, the snipped small PIBs-based disks can recover itself from mechanical damage after several-hour contact at room temperature.

Covalent polymers containing coordination complexes also have studied for making self-healing materials. Taking advantage of coordination interactions between catechol and ferric ions, researchers developed pH-controlled self-healing supramolecular polymers. The formation of mono-, bis- and triscatehchol-Fe³⁺ complexes can be manipulated by pH, of which the bis- and triscatehchol-Fe³⁺ complexes show elastic moduli as well as self-healing capacity. For example, the triscatehchol-Fe³⁺ can restore its cohesiveness and shape after being torn. Chain-folding polyimide and pyrenyl-end-capped chains give rise to supramolecular networks.

Optoelectronic

To achieve the light-to-charge conversion is the prerequisite step in artificial photosynthesis systems. By incorporating electron donors and electron acceptors into the supramolecular polymers, a number of artificial systems, including photosynthesis system, can be constructed. Owing to the existence of more than one interactions (π-π interaction, hydrogen bonding interaction and the like), electron donor and electron acceptor can be held together in a proper proximity to afford long-lived charge separated states. Then a light-to-charge conversion system with faster photoinduced electron transfer and higher electron-transfer efficiency can be achieved in these artificial polymers.

Biocompatible

It is quite common that biomolecules, such as DNA, protein and the like, come into being through various noncovalent interactions in biological system. Likewise, supramolecular polymers assembles themself via a combination of noncovalent interactions. Such formation manner endows supramolecular polymers with features, being more sensitive to external stimuli and able to render reversibly dynamic changes in structures and functions. By modifying monomeric units of supramolecular polymers with water-soluble pendants, bioactive moieties as well as biomarkers, supramolecular polymers can realize various kinds of functions and applications in biomedical field. At the same time, their reversible and dynamic nature make supramolecular polymers bio-degradable, which surmounts hard-to-degrade issue of covalent polymers and makes supramolecular polymers a promising platform for biomedical applications. Being able to degrade in biological environment lowers potential toxicity of polymers to a great extent and therefore, enhances biocompatibility of supramolecular polymers.

Biomedical applications

With the excellent nature in biodegradation and biocompatibility, supramolecular polymers show great potential in the development of drug delivery, gene transfection and other biomedical applications.

Drug delivery: Multiple cellular stimuli could induce responses in supramolecular polymers. The dynamic molecular skeletons of supramolecular polymers can be depolymerized when exposing to the external stimuli like pH in vivo. On the basis of this property, supramolecular polymers are capable of being a drug carrier. Making use of hydrogen bonding between nucleobases to induce self-assemble into pH-sensitive spherical micelles.

Gene transfection: Effective and low-toxic nonviral cationic vectors are highly desired in the field of gene therapy. On account of the dynamic and stimuli-responsive properties, supramolecular polymers offer a cogent platform to construct vectors for gene transfection. By combining ferrocene dimer with β-cyclodextrin dimer, a redox-control supramolecular polymers system has been proposed as a vector. In COS-7 cells, this supramolecular polymersic vector can release enclosed DNA upon exposing to hydrogen peroxide and achieve gene transfection.

Adjustable mechanical properties

Association and dissociation kinetics for polymer dynamics

1. Basic Principle : Noncovalent interactions between polymer molecules significantly affect the mechanical properties of supramolecular polymers. More interaction between polymers tends to enhance the interaction strength between polymers. The association rate and dissociation rate of interacting groups in polymer molecules determine intermolecular interaction strength. For supramolecular polymers, the dissociation kinetics for dynamic networks plays a critical role in the material design and mechanical properties of the SPNs(supramolecular polymer networks). By changing the dissociation rate of polymer crosslink dynamics, supramolecular polymers have adjustable mechanical properties. With a slow dissociation rate for dynamic networks of supramolecular polymers, glass-like mechanical properties are dominant, on the other hand, rubber-like mechanical properties are dominant for a fast dissociation rate. These properties can be obtained by changing the molecular structure of the crosslink part of the molecule.
2. Experimental examples : One research controlled the molecular design of cucurbit[8]uril, CB[8]. The hydrophobic structure of the second guest of CB-mediated host-guest interaction within its molecular structure can tune the dissociative kinetics of the dynamic crosslinks. To slow the dissociation rate (kd), a stronger enthalpic driving force is needed for the second guest association (ka) to release more of the conformationally restricted water from the CB(8] cavity. In other words, the hydrophobic second guest exhibited the highest Keq and lowest kd values. Therefore, by polymerizing different concentrations of polymer subgroups, different dynamics of the intermolecular network can be designed.For example, mechanical properties like compressive strain can be tuned by this process. Polymerized with different hydrophobic subgroups in CB[B], The compressive strength was found to increase across the series in correlation with a decrease of kd, which could be tuned between 10–100MPa. NVI, is the most hydrophobic subgroup structure of monomer which have two benzene rings, on the other hand, BVI is the least hydrophobic subgroup structure of monomer via control group. Besides, varying concentrations of hydrophobic subgroups in CB[B], polymerized molecules show different compressive properties. Polymers with the highest concentration of hydrophobic subgroups show the highest compressive strain and vice versa.

Biomaterials

Supramolecular polymers with specific, directional, tunable and reversible non-covalent interactions should be advantageous for biomaterials as well as biomedical applications. For instance, the reversible nature of supramolecular polymers can produce biomaterials that can sense and respond to physiological cues, or that mimic the structural and functional aspects of biological signaling. On the basis of their formation mechanisms, supramolecular biomaterials can be broadly classified as: (1) materials prepared from one-dimensional assemblies of molecular stacking motifs as in the case of peptide amphiphiles introduced by Samuel I. Stupp, and (2) materials prepared through chain extension of oligomers or through crosslinking of polymeric precursors by specific supramolecular recognition motifs.

Rationally designed supramolecular polymers-based polymers can simultaneously meet the requirements of aqueous compatibility, bio-degradability, biocompatibility, stimuli-responsiveness and other strict criterion. Consequently, supramolecular polymers can be applied to the biomedical field as a robust system. Other than applications mentioned above, other important and fascinating biomedical applications, like protein delivery, bio-imaging and diagnosis and tissue engineering, are also well developed.

Conceptual expansion

Unconventional monomers

Over the time, methods for supramolecular polymerization has expanded, and the range of its useable monomers has diversified. In addition to plethora of molecular motifs, biomolecules such as DNA, DNA nanostructures and proteins as well as inorganic objects as unconventional monomers has recently been investigated for supramolecular polymerization. In all of these cases, monomers are in much higher size, usually several nanometers, and the non-covalent interactions varies from hydrogen bonding, host-guest and metal coordination. A notable example is Mg^2+-assisted multivalent supramolecular polymerization of ATP-responsive biomolecular machines, chaperonine GroEL, resulting in a highly stable protein nanotube. Importantly, this nanotube shows an ATPase activity and dissociates into short-chain oligomers when treated with ATP because of the opening/closing motions of the constituent GroEL units.

Unconventional media

Supramolecular polymers usually prepared in solution. However anomalous polymeric properties can be expected when these polymers are prepared without a conventional organic or aqueous medium. For instance, liquid crystal media may affect the elementary steps of supramolecular polymerization as demonstrated by Takashi Kato in 1998, in the supramolecular crosslinking polymerization of physical gelators, which form a liquid crystal physical gel. When monomers are designed to be highly affinitive toward the LC media, supramolecular polymerization causes an order-increasing phase transition, resulting in a core-shell columnar LC. Supramolecular polymers can also be prepared in the solid-state, for instance, a nucleobase-appended telechelic oligomer as a monomer, resulted in the formation of 1D fibers upon cooling from its hot melt. As a new class of materials, supramolecular polymers formed at electrode and at the interface also become available.