{"paper_id":"f954e59a-39b7-4735-9698-2d3f3429ad92","body_text":"Many aspects of human well-being are\nrelated to the extent to which\none can control and plan one’s life. Unplanned and often unwanted\npregnancies can have a significant effect on spendable income, education,\nhealth, etc. An increased availability of contraceptives for both\nmen and women will lead to an increased opportunity for people to\nplan their lives and focus on their health and well-being before acquiring\nthe responsibilities of parenthood.\nFamily planning can lead to a decrease in one’s personal\nfinancial strain, decreasing the likelihood of individual poverty\nby eliminating the need to provide for additional, unplanned family\nmembers. By decreasing a country’s population, the extent of\ncountrywide poverty could also potentially be reduced.\nThe increased availability of contraception is likely\nto lead to\na decrease in the population size worldwide. If this is the case,\nthis will reduce all disadvantages and negative effects that are associated\nwith the exponentially increasing population growth, such as environmental\ndegradation, limited resource availability, etc.\nAs women are\nnaturally the most affected by unplanned pregnancies,\nthe issue strongly contributes to gender inequality. The availability\nof a desirable and efficient male contraceptive will allow men to\ncontribute to the prevention of unplanned pregnancies, reducing this\ninequality and improving the lives of both men and women. Contraception\nhas been around for decades and has naturally targeted the child-bearing\nhalf of couples. There has, however, been an increased interest among\nmen in contributing to the prevention of unwanted pregnancies. \n ,\nThe purpose of this comprehensive but not exhaustive literature\nreview is to explore the potential of hydrogel technologies for contraceptive\napplications and to identify their underlying mechanisms of action.\n\nThe oldest known method of contraception\nis likely “coitus\ninterruptus”, a natural method relying on the male partner\nwithdrawing his penis from the vagina prior to ejaculation.  Since then, researchers have made significant\nadvancements from this method toward more reliable methods including\nbarrier methods (male and female condoms), intrauterine devices (IUDs),\nhormonal contraception, and sterilization ( Figure  \n ).\nSome of the\ncurrently available contraceptive options for females\n(left) and males (right) (image created by using BioRender).\nAccording to the World Health Organization, condoms\nhave been reported\nto have a 13% fail rate. IUDs are not accepted by all bodies and can\ncause discomfort. Hormonal contraceptives often lead to negative side\neffects, and sterilization, such as vasectomy or tubal ligation, is,\nin most cases, a permanent procedure. In addition to these limitations,\nthe majority of contraceptives currently available target female contraception,\nas can be seen by the large number of examples provided for females\nin  Figure  \n , versus\nthe limited examples available for males. Much discussion has already\ntaken place about the limitations of the currently available methods,\nand improvements to these limitations may lead to an increased use\nof contraceptives due to user satisfaction and may result in the reduction\nof unintended pregnancies.\nImprovements\ncould include the reduction of side effects of hormonal\nmethods and making these methods more user-friendly, reliable, comfortable,\nand confidential.  In an attempt to achieve\nthese improvements, researchers have started focusing on nonhormonal\noptions and/or noninvasive approaches. Hydrogels may prove to be a\npromising solution.\n\nHydrogels are water-insoluble\npolymer networks with the ability\nto absorb vast amounts of bodily (aqueous) fluids. These polymer networks\nwere first developed as hydrogels by Wichterle and Lim in 1960, whereby\nthey were described as structures that can contain a particular amount\nof water, are biologically compatible, and are permeable to metabolites.  In order to have these properties, the hydrogels\nmust have hydrophilic moieties present in their three-dimensional\nstructure that become hydrated in aqueous media. \n − \n \n \n  They must be three-dimensional\nand cross-linked in such a way as to prevent dissolution.  Due to their large water content, hydrogels are\nhighly flexible, similar to natural tissue.  The volume of the hydrogel is determined by its water content, which\nshould remain constant at equilibrium, and is dependent on the structure\nof the polymers used, as well as the number of cross-links.  The first clinical application of hydrogels was\nthat of soft contact lenses.  Nowadays,\nhydrogels find themselves in numerous applications, including but\nnot limited to agriculture (soil conditioning and controlled release\nof fertilizers), environmental applications (water purification and\npollutant adsorption), diapers, and personal care products ( Figure  \n ). These applications\nhave been extensively reviewed, including reviews by Ullah et al.\nand Thakur et al. \n ,\nSome Applications of Hydrogels.\nAs has recently been reviewed by Chamkouri et al.,\nhydrogels have\ngained significant interest in various biomedical applications (drug\ndelivery, tissue engineering, and wound healing) because of their\nsoft structure, water absorption ability, resemblance to the extracellular\nmatrix (ECM), and their biocompatibility.  Injectable hydrogels intended for medical applications must be biocompatible,\nnontoxic, stable, and biodegradable, and have good viscosity, as well\nas suitable mechanical properties, among other essential properties. \n , \n  Furthermore, the hydrogel structure must be compatible with cells,\ntissues, and body fluids. \n , \n  Upon degradation, it\nis important that degradation products are also biocompatible and\nhave a low toxic potential.\n\nThe classification of\nhydrogels has been extensively studied and\nreviewed. Hydrogels can be classified based on their origin, namely,\nnatural, synthetic, and hybrid hydrogels. These hydrogels are derived\nfrom natural, synthetic, and a combination of natural and synthetic\npolymers, respectively. Natural hydrogels, made from natural polymers\nsuch as cellulose or chitosan, are nontoxic, biocompatible, and biodegradable,\nwhereas synthetic hydrogels, made from synthetic polymers such as\npoly­(ethylene glycol) (PEG), have the advantages of increased ability\nto absorb water, longer life, and increased gel strength.  The biocompatibility of these synthetic hydrogels\nis determined by the polymer units used to form the hydrogel.\nHydrogels can be classified based on composition, namely, homopolymeric,\ncopolymeric, and multipolymer interpenetrating polymeric hydrogels.\nHydrogels can be classified based on ionic charge, namely neutral,\nionic, and ampholytic hydrogels, which carry no charges, cationic\nor anionic charges, or both types of charges, respectively. Cationic\nhydrogels show increased swelling at lower  p H, whereas\nanionic hydrogels show increased swelling at higher  p H. Hydrogels can be classified in terms of porosity, namely nonporous,\nmicroporous, and superporous hydrogels. Hydrogels can be classified\naccording to their physical structures and chemical composition. Here,\nthey are divided into amorphous (or noncrystalline) and semicrystalline\nhydrogels, whereby amorphous hydrogels are characterized by randomly\ndistributed polymer chains, and semicrystalline hydrogels are characterized\nby a combination of amorphous and crystalline regions within the gel.\nFurthermore, hydrogels can be classified based on the type of external\nstimulus (or stimuli) they are capable of responding to.  Stimuli-responsive hydrogels can be classified\nbased on their response mechanism to various external stimuli. External\nstimuli could include physicochemical stimuli such as  p H ( p H-responsive hydrogels), temperature (thermoresponsive\nhydrogels), light (photoresponsive hydrogels), and electric and magnetic\nfields (electro- and magneto-responsive hydrogels), as well as other\nstimuli such as ultrasound irradiation, redox reactions, or the presence\nof enzymes, metals, small molecules, and proteins (entity-responsive\nhydrogels). Some hydrogels can undergo changes when exposed to multiple\nexternal stimuli (multistimuli-responsive hydrogels).\nFinally,\nhydrogels can be classified based on their mechanism of\ncross-linking, namely, physical and chemical cross-linking. The presence\nof cross-links is required for the network to remain intact. Physical\ncross-linking can include entanglements, ionic interactions, and hydrogen\nbonding, whereas chemical cross-linking involves the formation of\ncovalent bonds between cross-linked polymers. \n , \n  Chemically\ncross-linked hydrogels may be advantageous as they possess improved\nstability over physically cross-linked hydrogels and may provide better\nmechanical strength; however, this is not always the case as both\nphysically and chemically cross-linked hydrogels span a wide range\nof different properties. \n , \n  To compete in biocompatibility\nwith physical hydrogels, toxic cross-linking agents must be avoided\nin the synthesis of chemical hydrogels.\nChemical cross-linking\ninvolves various reactions such as photochemical\ncross-linking, enzymatic reactions, and click reactions, whereas physical\ncross-linking involves modification of intramolecular forces including\nelectrostatic forces, hydrogen bonding, and hydrophobic interactions\nby the use of ionic cross-linking, temperature-dependent methods,\nand  p H-dependent methods, among others. A summary\nof these reactions and interactions can be found in the reviews by\nAkhtar et al. and Chamkouri et al. \n , \n  The advantages\nof some of the biocompatible reactions and mechanisms are briefly\nsummarized in  Table  \n . As these reactions are biocompatible, they could be used for cross-linking\nhydrogels in situ, as well as for hydrogels that are preformed outside\nthe body and then applied, post-formation, to a specific application.\nThe cross-linking process used affects the physical properties of\nthe resulting hydrogel (mechanical strength, heat resistance, and\nsolvent resistance).\nNote that not\nall abiotic photochemical\nreactions and click reactions are biocompatible.\n\nImportant properties\nof hydrogels to be considered are the swelling\nratio and water absorption of the hydrogel, their mechanical properties,\nand their biological properties.  The degree\nof hydrogel swelling is directly linked to the degree of cross-linking.  Mechanical properties include but are not limited\nto elasticity and strength, whereas thermal properties include phase\ntransition temperature among other properties. The rheological behavior\nof hydrogels, i.e., their flow and deformation characteristics, is\nof importance when designing a hydrogel for a specific application.\nThese characteristics determine how the hydrogel can be administered,\nstored, and used. All of these properties must be determined during\nthe characterization of hydrogels. The characterization of these properties\nhas been extensively reviewed.\n\nFor the biodegradability of\nhydrogels, labile bonds are incorporated\ninto either the network backbone or in the cross-links.  These bonds can be cleaved under physiological\nconditions using different procedures including solubilization, chemical\nhydrolysis, enzymatic hydrolysis, ionization or ion exchange, and\nphotochemical deprotection. \n − \n \n  There has been a movement from\nstatic hydrogel systems that follow simple degradation to dynamic\nhydrogel systems that respond to internal biological or external signals\nwith spatial precision.  Hydrogels of\nparticular interest for wound management, for example, are those that\ncan cross-link in situ and dissolve on-demand using physical or chemical\nreactions.  In general, hydrogels for\nbiological applications must mimic the viscosity and stiffness of\nthe surrounding tissues and allow for the selective permeation of\nessential cells and nutrients. This is required to prevent negative\ncellular responses to abnormal mechanical signaling.\n\nThe use of hydrogel technology\nin contraception is a relatively\nnew area of research with great potential. In a study conducted by\nHardy et al., a total of 635 women (including adolescents and adults\nfrom low and middle-high socioeconomic groups) were interviewed on\ntheir preferences for different dosage forms (gels, creams, tablets,\nfoams, films, and suppositories) of contraceptive formulations. The\nresults of this study indicated that the majority of women (40% of\nthe candidates) preferred gels over other vaginal formulations.  The way in which a formulation provides contraception\nmay influence the acceptance (individually or culturally) of a contraceptive\nmethod.\nUnderstanding the mechanism of action (MOA) of contraceptive\nmethods\nis important when developing new methods or improving existing formulations.\nThe MOA behind hydrogels as contraceptives has not been discussed\nin depth. There are several different MOAs behind hydrogel contraceptives,\neach with its advantages and disadvantages, that are being explored\n( Table  \n ). The most\ncommon of these MOAs include physical barriers, spermicidal effects,\ncontrolled drug release, and combination approaches ( Figure  \n ). There are several other\nless common MOAs being investigated, including immunological approaches,\nsperm immobilization, cervical barrier enhancement, and targeted delivery.\nThe specific MOA for a particular hydrogel-based contraceptive depends\non its composition and design and most of these contraceptives are\neither in early stages of development, or still in pre-clinical or\nearly clinical trials. Ongoing research to optimize the properties\nof these hydrogels to improve on biocompatibility, biodegradability,\nand controlled release duration, as well as further evaluations of\ntheir safety and efficacy is, in most cases, still required.\nMost common mechanisms of action. A: Physical barrier\nMOA –\nprevention of sperm from reaching an egg cell; B: Controlled drug\nrelease MOA – drug-loaded hydrogel releasing drugs over time\nor due to an external trigger; C: Spermicidal effects MOA –\nacidic environment leads to loss of sperm function, nonoxynol-9, a\ncommon spermicide used in contraceptives, and repulsive electrostatic\nforces on hydrogel affecting sperm mobility (Images created using\nBioRender).\n\nIn the physical\nbarrier MOA, hydrogels can be used as occlusive\ndevices, whereby they act as physical barriers somewhere within the\nreproductive tract, inhibiting the movement of sperm ( Figure  \n ).  Hydrogels that can form in situ can solidify within the vagina (typically\nthe fallopian tubes), or within the vas deferens, creating a physical\nbarrier and blocking the passage of sperm ( Figure  \n ). Increased cross-linking density leads\nto stiffer gels with smaller pore sizes and, hence, decreased particle\nmobility.  The method by which the hydrogel\nis formed, the polymer concentration within the gel, as well as the\nhydrogels’ responses to stimuli, may affect its pore size and\nmust be taken into account when designing a hydrogel as an occlusive\ndevice.  The physical barrier mechanism\nis ideal for designing simple hydrogels that could be used by both\nmen and women, as they do not include the use of hormones or drugs\nthat are specific to each sex.\nHuman reproductive systems (left, female;\nright, male) (image created\nusing BioRender).\nIn the early 1980s, the\nfirst occlusive hydrogel device for this\napplication was studied. RISUG (Reversible Inhibition of Sperm Under\nGuidance) is a “non-occlusive” styrene maleic anhydride\nproduct that lines the vas deferens, using an apparent change in  p H to create a “positively charged” complex\nthat disrupts the sperms’ acrosomal layer, preventing fertilization\nfor up to 10 – 15 years. \n − \n \n \n \n  This intravas injection technology was studied in nonhuman primates\nand was found to effectively prevent fertilization and could be successfully\nreversed with a vibratory/percussive massage.\nGuha suggested that the proposed MOA involves the formation\nof\na positively charged SMA-DMSO-amino acid complex that leads to the\ndisruption of sperm surface enzymes and lipid domains, increasing\nthe membrane fluidity and, in turn, destabilizing the sperm membranes,\nessentially causing a loss of fertility. It was proposed that the\nlow  p H conditions caused by the complex, in combination\nwith the complex electrical charges of the polyelectrolyte system,\nmay produce sperm abnormalities and hence affect fertility.  These effects were hypothesized to be enhanced\nin the presence of proteins from bodily fluids.  This hypothesized MOA has not yet been confirmed. The contraceptive\nMOA is more likely that of a physical barrier, whereby the hydrogel\nis used to block the passage of sperm.\nThe reversibility involving\neither the injection of a DMSO or sodium\nbicarbonate solution, or percutaneous squeezing of the vas deferens,\nalong with electrical stimulation and vigorous massaging of the hydrogel,\nhas been successfully shown in numerous animal studies but has not\nyet been studied in humans.  This product\nhas been studied over several decades and has undergone multiple animal\nstudies (rats, rabbits, and monkeys) and human clinical trials; however,\nit has never been brought to market.\nThe P-block, Mark 9, was developed in the 1980s (around the same\ntime as RISUG developments started) by Brundin et al. as an occlusive\nintrauterine contraceptive. \n , \n  It was described as\na “hydrogelic intratubal device” that was inserted hysteroscopically\ninto the fallopian tubes, whereby the dried hydrogel swelled in the\npresence of bodily fluid to prevent intratubal and intrauterine pregnancies.\nThis formulation is different from the RISUG formulation, whereby\nit is inserted as a preformed (dried) gel, as opposed to an in situ-forming\nhydrogel. The device consisted of a nylon-6 core on which a hydrogelic\nbody was attached by copolymerization using γ-irradiation. The\nP-blocks were successfully inserted into 22 women, whereby none of\nthem became pregnant for up to 6 months after insertion. The P-block,\nMark 9, was designed as an occlusive device; however, the exact nature\nof the antifertility action is still unknown. It was designed for\npermanent contraception; however, after removal, successful pregnancy\nwas observed.\nIn 1994, Maubon et al. developed and tested an\nocclusive hydrogel\nimplant consisting of a copolymer of acrylonitrile dissolved in DMSO\nand saline, certain dyes, and a sclerosing agent (for tubal wall alteration)\nin rabbits.  The intrauterine device showed\npromise for contraception in female rabbits; however, it was found\nto have negative side effects such as tubal inflammation, and the\nhydrogel was not mechanically strong enough, whereby it fragmented\nin the tube and did not remain intact after insertion. Since the gel\nis mechanically weak, the tubal inflammation is likely due to the\nsclerosing agent, indicating that tubal wall alteration may not be\nthe most ideal way to cause occlusion in the uterus or fallopian tubes.\nUshercell, a uniquely high molecular weight form of sodium cellulose\nsulfate, was developed in 2002 and evaluated in phase 1 clinical trials\nas a contraceptive antimicrobial agent by Anderson et al.  It is active against both spermatozoa and multiple\nsexually transmitted infections (STIs) including HIV, chlamydia, and\nherpes, and has been shown to be nontoxic and to have an acceptable\nsafety profile via preclinical toxicity studies.  This patented product was found to be an effective contraceptive\nwhen vaginally applied, and the mechanism of contraception is still\nunknown. It was hypothesized to have several effects on sperm function,\nultimately immobilizing sperm, as well as acting as a barrier, preventing\nthe penetration of sperm in cervical mucus; however, additional studies\nare required to confirm the possible MOA of contraception of Ushercell.\nThe additional antimicrobial properties of the hydrogel make it more\ndesirable as a contraceptive.\nIt was shown to prevent conception\nin rabbits when added to sperm,\nas well as when applied to the vagina prior to insemination.  Further studies of Ushercell indicated that\nit is a reversible, effective, long-lasting (up to 24 h) contraceptive\nat relatively low concentrations (6% cellulose sulfate gel).  Furthermore, the safety and efficacy of the\n6% cellulose sulfate gel were studied in humans, and it was found\nto be safe for use twice daily over a two-week period.  Phase 3 clinical trials of Ushercell as an HIV\nmicrobicide were stopped when it was found to increase the rate of\nHIV infection in the women enrolled in the randomized trial.  The increased rate of HIV infection in women\nwho used Ushercell indicates the importance of hydrogels undergoing\nvarious tests (including those related to STIs) before being commercialized,\nto identify the increased risks associated with using hydrogels for\ncontraceptive purposes. This would include hydrogels that are not\ndesigned for STI prevention or treatment, as the presence of the hydrogel\nor the damaging effects it may have on the surrounding tissue may\nlead to an increased risk for infection.\nVasalgel, another intravas\ninsertion product, was developed in\n2011 by the Parsemus Foundation as a long-term, reversible contraceptive\nand is currently under further development as Plan A by NEXT Life\nSciences, a US-based biotechnology company. This technology uses a\nhigh molecular weight SMA acid polymer that is dissolved in DMSO,\nand upon insertion into the vas deferens, swells to fill the lumen,\nand acts as an occlusive device, preventing the passage of sperm upon\nejaculation.  The formation of Vasalgel\nrelies on nonsolvent-induced phase inversion, whereby, upon insertion\ninto the body, the DMSO is rapidly exchanged with bodily fluid, transforming\nthe polymer solution into a physically cross-linked hydrogel. Vasalgel\nhas been shown to reliably prevent the passage of sperm in different\nanimal studies and was proven to be reversible after over 1 year using\na sodium bicarbonate solution in a rabbit model. \n , \n  This product is expected to enter clinical trials in the near future\nand shows promise for commercialization. This formulation was based\non the original RISUG formulation.\nIn 2019, the RISUG formulation\nof SMA was investigated as a nonhormonal\nfallopian tube implant for female contraception.  The hydrogel exhibited selective antimicrobial activity\nas well as excellent biocompatibility in rats, and it was concluded\nthat the formulation showed great promise for the development of an\nintrauterine implant for female contraception. Furthermore, it was\nhypothesized that RISUG may impart potential anticancer properties\nand could, in addition to providing contraception, assist in the prevention\nof early-stage endometrial cancer post-implantation.  This hypothesis has not yet been validated by in vitro\nor in vivo studies. This formulation would be ideal if it could be\nused for both male and female contraception.\nIn 2020, Subramanian\net al. investigated a flexible block copolymeric\nscaffold of RISUG, blend-grafted with poly­(ethylene glycol)-modified\npolycaprolactone, for use as a biodegradable, nonhormonal, female\nintrauterine long-term contraceptive device.  In vitro studies showed that the spermicidal activity of the grafted\npolymeric scaffold increased as the concentration of SMA hydrogel\nwithin the scaffold increased. The blend was shown to be biocompatible\nin organ pathology tests and nontoxic to rat uterine cell lines. Further\ninvestigations to determine the long-term efficacy of contraception\nare yet to be done, as well as in vivo contraceptive studies.\nWurm et al. investigated the use of κ-carrageenan physically\ncross-linked hydrogels for the reversible occlusion of the vas deferens.  This formulation is different from most of the\nother hydrogel systems for contraceptive purposes, as it makes use\nof naturally derived polymers as opposed to synthetic polymers, which\ncould lead to increased biocompatibility. After extensive swelling\nstudies, it was found that the gels were feasible candidates for occlusion\nof the vas deferens.  They used a gel-tube\nmodel to test whether the hydrogel could be removed by using compressive\ndisintegration. They found that manually applied pinch forces were\nnot enough to completely disintegrate the gel matrices for reversal\nand removal of the gel in the modeled vessels. It was suggested that\ncompressive devices might assist in the disintegration of the hydrogels\nbut may result in undesired damage to surrounding tissue. Further\nbiocompatibility and toxicity studies are yet to be completed for\nthis formulation. This study focused on the very important aspect\nof ease of reversal/removal, which many other studies did not focus\non. Chemical reversal would likely cause less damage than physical\nreversal and should be considered for future formulations.\nAdam\nis a more recent hydrogel technology developed around 2022\nby a US-based biotechnology company, Contraline. This hydrogel acts\nas an occlusive device within the vas deferens and is based on a two-component\naqueous system that, once mixed, forms a hydrogel. This product has\nalready entered human clinical trials, whereby, after the injection\nof the technology into 23 men in Australia, the sperm count was reduced\nby 99–100%. This contraceptive has been tested in an animal\nstudy and was shown to last up to 2 years, with the option of being\nreversed at an earlier stage. The reversal has, however, not yet been\ntested in humans. The chemistry behind this technology is based on\na PEG polymer system cross-linked by thiol-maleimide click reactions. \n ,\nAn alternative two-component aqueous system based on modified\nSMA\nand a PEG-based cross-linker was developed by Klumperman and coworkers.  The chemically cross-linked hydrogel contains\nthioesters within its cross-links, which can be reversed through native\nchemical ligation to redissolve the hydrogel on demand.  This patented technology is still in its early\ndevelopmental stages. Wang et al. developed an ultrasound-induced\nself-clearance hydrogel composed of sodium alginate conjugated with\nreactive oxygen species-cleavable thioketal, titanium dioxide, and\ncalcium chloride.  TiO 2  was\nused as a sonosensitizer to generate the reactive oxygen species after\nultrasonification, and CaCl 2  was used to trigger the hydrogel\nformation. A solution of these materials was injected into the vas\ndeferens and formed a hydrogel in situ within 160 s. The reversal\nrelied on the use of remedial ultrasound, which triggered the production\nof reactive oxygen species by titanium dioxide, which inherently cleaved\nthe sodium alginate-thioketal conjugate, resulting in the dissolution\nof the hydrogel. The insertion and reversal of the hydrogel could\nbe monitored by using diagnostic ultrasound. This technology was evaluated\nin vivo using pubescent SD rats, and effective contraception was achieved.\nFertility after reversal using remedial ultrasound was completely\nrestored.  This formulation includes commonly\navailable methods for visualizing implantation and reversal within\nits design, which adds a level of superiority over other formulations\nthat do not include methods for visualization. This is an important\nconsideration, as confirmation of insertion (and removal) of a contraceptive\nis imperative for ensuring successful prevention of conception. The\ncomplexity of the formulation could possibly lead to increased costs\nin production as well as an increased risk of failure of gelation\nor reversal.\nAnthis et al. developed a stimuli-responsive hydrogel\nas a reversible\nmechanical female contraceptive that could also be used for endometriosis\ntreatment.  The hydrogel was designed\nto reversibly occlude the fallopian tubes and was comprised of two\ndifferent acrylamide-based polymers cross-linked with a disulfide\ncross-linker ( N,N ’-bis­(acryloyl)­cystamine)\nor a photolabile poly­(ethylene glycol) diphotodegradable acrylate\ncross-linker, whereby noninvasive reversal (within 30 min) used disulfide-reducing\nagents and near-visible UV light, respectively. The hydrogels were\ninserted as dried hydrogel materials, which swell in the presence\nof bodily fluid to fill a portion of the fallopian tube, ultimately\npreventing the passage of sperm, as well as endometrial cells. The\nhydrogels were found to be biocompatible and noncytotoxic when tested\nin fresh porcine fallopian tubes and could easily be inserted using\nreadily available gynecological tools. Insertion could be visualized\nusing ultrasound guidance. Further in vivo human clinical studies\nare required to confirm the compatibility and functionality of the\ngel, as well as to determine the integrity of the fallopian tube after\nreversal. Furthermore, post-removal fertility must also be investigated.\nThis formulation also includes methods for visualization during insertion,\nwhich makes it easier to confirm successful contraception. These last\ntwo formulations are very quick to insert, as well as to remove, making\nthe procedures involved during insertion and removal more cost-effective\nand less invasive. The added visualization aspects make them both\nmore appealing than the other formulations.\n\nHydrogels that are acidic in nature can be used to lower the  p H of the vagina, creating a hostile environment for sperm,\nleading to reduced motility or immobilization and reduced viability.  Repulsive electrostatic forces can also inhibit\nparticle mobility in hydrogels, further increasing their ability to\nblock the flow of charged particles.  Alternatively,\nthe hydrogels can be loaded with spermicides/sperm-killing agents,\nallowing for sustained release and localized action, leading to sperm\ndestruction ( Figure  \n ). Many of the gels with spermicidal properties need to be used in\nconjunction with an additional contraceptive due to the low efficacy\nof contraception on their own. Contraceptives that have spermicidal\nand/or hormonal effects require additional tests for FDA approval\nand are, therefore, more costly to study for use inside the human\nbody.\nIn 1982, Singh et al. investigated the use of a poly­(2-hydroxyethyl\nmethacrylate- co -methacrylic acid), poly­(HEMA-MAA),\nhydrogel for use as a male contraceptive.  The polymer solution consisting of poly­(HEMA-MAA) dissolved in DMSO\nis inserted into the vas deferens, whereby the DMSO and water are\nexchanged, resulting in the formation of a hydrogel. Spermicidal action\nin vitro studies indicated that sperm became immediately immotile\nwhen in contact with the hydrogel, and it was concluded that the spermicidal\naction was due to the low  p H environment caused by\nthe presence of the carboxylic acid moieties from the methacrylic\nacid repeat units. In vivo fertility action was tested using rats,\nand the results indicated that, in the presence of the hydrogel, no\nfertility was observed. The presence of dead, whole, or decapitated\nsperm in vaginal smears post-coitus indicated that the hydrogel did\nnot act as a barrier but rather with spermicidal effects to hinder\nfertility. The intravasal gel was able to be flushed out with DMSO.\nBufferGel was developed by ReProtect, LLC, as an aqueous vaginal\ngel with a  p H of 3.9, equipped with an acidic buffering\naction designed to hinder vaginal neutralization by semen and, hence,\nact with an irreversible spermicidal effect. \n , \n  This high-molecular-weight, cross-linked, poly­(acrylic acid) gel\nhas the ability to buffer twice its volume of semen to a  p H lower than 5 due to its active ingredient, the hydrogen ion. Not\nonly is BufferGel spermicidal, but it is also virucidal to HIV and\nherpes simplex virus type 2, among other STIs. This gel was shown\nto have a low toxicity profile, and minimal side effects were observed\nby those who underwent clinical trials (low-risk, abstinent women\nand monogamous women). The most common adverse side effect was irritative\ngenitourinary symptoms.  Further evaluation\nof the contraceptive efficacy of BufferGel in humans is still required,\nincluding postcoital tests and contraceptive trials; however, the\ncontraceptive efficacy of BufferGel with a cervical barrier (such\nas a diaphragm) has been tested.  Furthermore,\nthe BufferGel Duet, a buffering microbicide and spermicide gel applied\nto the cervix via a novel applicator, was developed and tested, and\nthe study indicated successful use and application of the applicator,\nshowing feasibility for further development of this technology.\n\nThe spermicidal\nMOA is related to controlled drug release. The\ncontrolled drug release MOA can be either hormonal or nonhormonal.\nIn hormonal controlled drug release, hydrogels can encapsulate hormones\nlike progesterone, which inhibit ovulation or thickening of cervical\nmucus, and slowly release these hormones, leading to decreased chances\nof fertilization ( Figure  \n ). Nonhormonal options can include other compounds with contraceptive\neffects, such as antiprogestins, which prevent implantation, or vasodilators,\nwhich cause blockages in the vas deferens.\nIn 1993, Shantha\net al. designed a biodegradable hydrogel based\non poly­(ethylene glycol) (conjugated with/forming a physical adduct\nwith collagen) and poly­( N -vinylpyrrolidone), externally\ncross-linked using hexamethylene diisocyanate to be used as a reversible,\nhormonal male contraceptive.  The hydrogel\nwas loaded with testosterone, a male contraceptive steroid, and showed\na zero-order release profile after an initial burst release for up\nto 90 days, after which the study was discontinued. The downfall to\nthis formulation could be the incorporation of high levels of testosterone,\nas increased testosterone levels in men may lead to adverse side effects\nand an increased risk of complications.\nD’Cruz et al.\ndescribe gel-microemulsions that could be\nused as intravaginal/rectal delivery vehicles for pharmaceutical drugs\nwith activity against STIs, as well as those that exhibit spermicidal\nactivity in human semen.  The contraceptive\nefficacy of the gel-microemulsions was proven in rabbit model studies,\nand intravaginal toxicity was tested in rabbits and mice, where the\nformulations were found to be safe and nontoxic. These gel-microemulsions\nare to be used continuously and are not “permanent but reversible”,\nwhich leads to similar issues that are currently faced with the use\nof condoms such as failure to use them correctly, if used at all.\nThe use of gels in vaginal drug delivery systems was reviewed in\n2006 by das Neves et al., whereby the use of vaginal gels as contraceptives\nwas briefly discussed.  A few examples\nof gels loaded with spermicidal drugs or contraceptive agents and\ngels with acid-buffering capabilities were mentioned, including some\nmarketed vaginal contraceptive gels such as Advantage-S, Conceptrol,\nand Gynol (II) (all loaded with nonoxynol-9 as the contraceptive agent).\nAgain, the use of gels as a delivery system for contraceptive drugs\nis typically designed to be temporarily used prior to or immediately\nafter intercourse, which may lead to failed contraception due to incorrect\nuse/application.\nNonoxynol-9 ( N -9) has been\nused over the past\n60 years globally as a spermicide for the killing of sperm for contraceptive\npurposes ( Figure  \n ).\nIt has been shown to have multiple negative side effects but is the\nactive ingredient in multiple commercially available contraceptives.\nIt has been loaded into gels and, as such, has been used as a vaginal\ncontraceptive. The effect of  N -9 on sperm functions\nwas systematically reviewed by Xu et al., who summarized details of\nthe different delivery systems, including those of gels.\nJalalvandi et al. developed a  p H-responsive hydrogel\nbased on the mucoadhesive biopolymer, chitosan, for anticancer and\ncontraceptive purposes.  Fast- and slow-degrading\nhydrogels were developed (tuned using cross-linking density) and were\nloaded with a nonhormonal spermicide and an anticancer agent, namely\niron­(II) gluconate dihydride and doxorubicin hydrochloride, respectively.\nThe hydrogel is formed after insertion and degrades over time to release\nthe therapeutic agents intravaginally. For nonhormonal contraceptive\npurposes, the hydrogel is to be inserted inside the vagina prior to\nintercourse, whereby the spermicidal agent is quickly released. The\ncytotoxicity of the hydrogels was tested against mesenchymal cell\nlines and showed no cytotoxic effects. Further in vivo studies are\nstill required for in-depth cytotoxicity studies and mucoadhesive\nassessment.\nLong et al. developed a controlled-release system\nfor levonorgestrel,\nusing chemically cross-linked chitosan microspheres embedded in a\nphysically cross-linked poly­(vinyl alcohol) hydrogel for long-term\ncontraceptive delivery.  A zero-order\nrelease profile (without burst release) was obtained for the microsphere-hydrogel\nsystems, and this system was considered to be promising as a long-term\ncontraceptive delivery system. This type of once-off insertion with\nlong-term contraceptive delivery would be ideal over insertion prior\nto intercourse for short-term/immediate delivery.\nXie et al.\ndeveloped a promising carbomer-based trifunctional contraceptive\nhydrogel for intravaginal administration.  This contraceptive gel was loaded with three FDA-approved drugs,\nnamely tenofovir, gossypol, and nitroglycerin, which each play a role\nin the prevention of STIs, contraception, and male erectile function,\nrespectively. Gossypol was confirmed to inhibit sperm motility of\npig sperm samples and is hence the spermicidal agent released by the\nhydrogel. This gel was tested for its safety and functionality using\nmultiple in vitro experiments and was shown to successfully prevent\nconception in female rats when intravaginally applied and enhance\nerectile function in rats when applied to male genitalia. The inhibitory\neffect on STIs was not verified using animal models. This formulation\nis used prior to intercourse; however, it has the added benefit of\nenhancing erectile function, which may be appealing to men with erectile\ndysfunction or associated disabilities.\nRecently, much research\nhas gone into the use of microneedles for\nthe controlled release of therapeutics.  Microneedle patches have been developed for the slow controlled\nrelease of hormones for female contraceptive use. \n − \n \n \n  A particularly interesting type\nof microneedle is that of hydrogel-forming microneedles.  These have not yet been explored for contraceptive\nuse but should be considered during the design of new hydrogel-based\ncontraceptives.\nWang et al. synthesized a contraceptive drug-loaded\ncomposite hydrogel\ncomposed of modified cellulose (aldehyde-replaced oxidized regenerated\ncellulose) and chitosan, cross-linked via a Schiff base reaction.  The contraceptive drug, a drospirenone liposome,\nis poorly water-soluble; hence, its incorporation into a hydrogel\nallows for the controlled slow release of the drug and increased absorption\nand efficacy of the contraceptive, reducing side effects associated\nwith increased oral intake. The promising results indicated that the\nhydrogel was successfully synthesized and the drug was successfully\nloaded into the hydrogel, leading to improved drug solubility and\nstability.\n\nCombination approaches combine\ntwo or more mechanisms within one\nhydrogel formulation, potentially enhancing the efficacy of the hydrogels\nand providing increased prevention of unwanted pregnancy. Some of\nthe above-mentioned formulations could also be considered for the\ncombination approach MOA; however, they were classified according\nto their suspected primary cause of contraception.\nA cocktail-inspired\nmale contraceptive was developed by Bao et\nal., and it relies on both chemical and physical mechanisms for effective\ncontraception.  The hydrogel formulation\nis a mixture of sodium alginate, calcium carbonate, and gluconolactone,\nwhich make up the injectable hydrogel. EDTA is the agent used to provide\nchemical contraception, as it has the ability to inhibit sperm motility;\nhowever, it is also used to dissolve the hydrogel upon reversal. The\ncontraceptive formulation is inserted into the vas deferens by the\nsequential injection of PEG-Au nanoparticles (used as a temperature-switchable\nphysical barrier to encapsulate the EDTA), followed by EDTA (for sperm\ninhibition and hydrogel dissolution), another layer of PEG-Au nanoparticles,\nand finally the calcium alginate hydrogel (used as a long-term physical\nbarrier). Near-infrared irradiation is used for the reversal of the\nhydrogel, whereby after 5 min of irradiation, the PEG-Au nanoparticles\nmelt, allowing the EDTA to gradually dissolve the hydrogel, restoring\nfertility. This contraceptive method was shown to prevent conception\nin rats for more than 2 months, indicating that it is an effective\nmedium-term contraceptive. Further experiments are required to determine\nthe safety of the materials as well as to determine the exact duration\nof contraception. The complexity of this formulation may lead to increased\nvariables for potential failure.\n\nThe less common approaches require further studies to confirm the\nviability and efficacy. For example, immunological approaches can\ninclude hydrogels loaded with third-party modulators, such as antigens,\nthat can induce an immune response that specifically targets sperm\ncells, leading to infertility.  This approach\ncan face challenges in antigen design and safety. The idea of antispermatozoal\nantibodies was investigated by Jager and Kremer et al. \n − \n \n \n  Immunocontraception is not currently approved for human use; however,\nresearchers have been studying the use of hydrogels as delivery vehicles\nfor immunocontraceptives in animals.\nFor example, Bansal et\nal. developed an adjuvanted hydrogel-based  p DNA nanoparticulate\nvaccine for immunocontraception and\nrabies protection and tested it in mice.  The results indicated that after the mice were exposed to the hydrogel\nand nanoparticles, anti-GnRH antibodies (which cause the immunocontraceptive\neffect) were present for up to 12 weeks. Further studies on the efficacy\nof the nanoparticles in causing sterility in the animals are still\nrequired.\nWu et al. developed a thermoresponsive chitosan hydrogel\nfor use\nas an antirabies and immunocontraceptive vaccination.  Initial studies on the ERA-2GnRH vaccine alone indicated\nthat it successfully provided protection from the rabies virus and\nled to >80% infertility in mice after triplicate doses. The vaccine\nwas then loaded into a hydrogel for safer sustained release of a one-dose\ndelivery of the formulation, whereby the antirabies properties were\nimproved, but the contraceptive properties of the vaccination were\ncompromised. It was suspected that due to the slow release of the\ngonadotropin-releasing hormone antibodies, an upper threshold required\nfor contraception was not achieved. Further improvements on the formulation\nand delivery methods are required. This formulation is superior to\nthat developed by Bansal et al. as it includes antirabies properties.\nSince this MOA is not yet accepted for use in humans, it will likely\nonly be used in formulations that target animal sterilization. The\neffects of altering immune responses need to be studied in more depth\nbefore this type of technology is commercialized for widespread use\nin animals and/or humans.\n\nHydrogels can\nbe designed to have adhesive properties, leading\nto the capture and immobilization of sperm within the reproductive\ntract, or they could be loaded with chemoattractants, whereby, in\nboth cases, movement toward the egg is prevented.\nPatel et al.\ndesigned a curcumin-loaded in situ forming hydrogel\nfor female contraception utilizing a Box-Behnken statistical design\nfor optimization.  Poloxamers are copolymers\ncomposed of poly­(ethylene oxide) and poly­(propylene oxide) units,\nwhich have the ability to form gels near body temperature. Poloxamer\n407 (P407) is an ideal filler used in the preparation of temperature-sensitive,\nin situ forming gels, as it has good temperature sensitivity and biocompatibility,\nwhereas poloxamer 188 (P188) is used to regulate the gelation temperature.\nDifferent formulations of mixtures of P407/188 and a mucoadhesive\npolymer hydroxypropyl methylcellulose (HPMC K4M) were compared and\noptimized, and the final formulation was loaded with curcumin. When\nsubjected to sperm immobilization studies, the formulation was shown\nto successfully immobilize sperm within 11 s. The hydrogel was designed\nto be placed within the vagina, 30 min prior to intercourse, to allow\nsufficient time to release 50% of the drug to achieve contraceptive\nefficacy. It was hypothesized that both curcumin and poloxamer contributed\nto sperm immobilization. Preclinical studies are still required prior\nto testing in women. In addition to in vitro contraception, the dosage\nform could also be placed inside a condom for additional spermicidal\naction. Again, the hydrogel is intended to be used prior to intercourse,\nallowing for potential risks of failed contraception due to a failed\nor forgotten application.\nNot many hydrogel formulations have\nbeen developed to target this\ntype of mechanism of action, possibly because this mechanism of action\nis not effective on its own and may need to be coupled with additional\nmodes of action to ensure effective contraception. Further research\nis required to confirm this claim.\n\nHydrogels can be used to thicken or stiffen cervical mucus, creating\nanother type of physical barrier to sperm passage. This MOA is similar\nto existing cervical cap methods but has the potential for longer-lasting\nand/or more comfortable use. Saxena et al. describe a biodegradable\nhydrogel composed of dextran, copolymers of polylactide, and ε-caprolactone\nfor use as a nonhormonal, intravaginal contraceptive device.  The hydrogel was loaded with different spermiostatic\ndrugs in order to have multiple uses and effects. Iron­(II) α-gluconate\ndihydrate was used for the immobilization of the sperm tail due to\nlipid peroxidation; ascorbic acid was used to thicken the cervical\nmucus to prevent sperm penetration; mixtures of polyamino and polycarboxylic\nacids were used to maintain a vaginal  p H of approximately\n4.5. The combination of these drugs ensured that sperm was not motile\nand could not survive the vaginal environment. The hydrogel was shown\nto elute effective combinations of these drugs within 30 s for up\nto 16 days using sperm penetration tests, and in vivo studies were\ncarried out on rabbits indicating successful killing of sperm after\ninsemination. This is the only hydrogel formulation that was designed\nto enhance the cervical barrier to prevent the passage of sperm; however,\nit could also be classified under the combination approaches due to\nthe additional sperm immobilization properties.\n\nTargeted delivery MOA can potentially reduce systemic side effects\nof contraceptive drugs by allowing these drugs to be delivered directly\nto their target sites. This can be achieved by designing the hydrogel\nto adhere to specific cells or tissues or by designing a hydrogel\nthat is responsive to physiological changes, the latter allowing the\nrelease of the contraceptive drug (e.g., progesterone or levonorgestrel)\nonly in response to specific conditions such as hormonal fluctuations\nor the presence of sperm, indicated by changes in  p H or temperature, for example. Most examples of this kind found in\nthe literature suggest contraceptive applications; however, the hydrogels\nin question were not tested for specific contraceptive applications. \n ,\n\nMany different hydrogels\nas contraceptives have been designed and\ntested over the past couple of decades. The main issue that most of\nthese formulations have faced is biocompatibility and increased side\neffects. Many of the designed hydrogels caused discomfort or irritation\nin users. A comfortable, completely biocompatible option has yet to\nbe commercialized. One big hurdle for all researchers in this field\nis the requirement for essential preclinical and clinical trials,\nwhich are expensive and time-consuming. Many of the options that have\nreached clinical trials were abandoned due to the toxicity or negative\neffects experienced by the patients involved. The safety, efficacy,\nand regulatory hurdles stand in the way of researchers; however, these\nparameters and hurdles are very important and cannot be avoided in\nthe design of contraceptives, especially those that end up inside\nthe human body.\nIt is clear from  Figure  \n  that the majority (71%) of the hydrogels\ndesigned for contraceptive\nuse targeted female contraception, and the physical barrier and controlled\ndrug release mechanisms of action were the most common for both men\nand women. There is a clear gap in the research targeting hydrogels\nas male contraceptives, and many of the less common MOAs have little\nto no hydrogel designs published in the literature.\nComparison of mechanisms\nof action for hydrogel contraceptives\nfor different sexes *Publications were sourced from the PubMed NIH\ndatabase, using keywords “hydrogel contraception” searching\nthe literature published between 1973 and 2024. Furthermore, the Scopus\ndatabase, using keywords “hydrogel AND contraceptive OR contraception”\nsearching literature published on any date was also used. Additionally,\nreference lists of relevant papers were used as an additional source\nof papers.\nIncreased research in this field\nwill likely lead to an accepted\nand widely used nonhormonal contraceptive, for both men and women,\nthat avoids the complications involved with hormonal contraceptives.\nAn occlusive, nonhormonal medical device that is suitable for both\nmen and women would be an ideal output from this growing field of\nresearch.\n\nAlthough much research has been\nconducted on the use of hydrogels\nas contraceptives, the majority of the research has targeted female\ncontraception ( Figure  \n ). In addition to this, most of the hydrogels were not designed to\nbe used as a “permanent-but-reversible” contraceptive\nbut rather designed to be applied prior to intercourse.\nFrom\nthe research that has been conducted, it is clear that hydrogels\nhave great potential to act in a contraceptive manner and can also\nbe designed to include additional microbicidal and antiviral properties,\nadding to the advantages of using this type of technology as a contraceptive.\nUnderstanding the mechanisms of action of hydrogels as contraceptives\nis important for further optimizations and future designs. Hydrogels\nas contraceptives form a promising, understudied research avenue with\ngreat potential for both male and female contraception. Research into\nthe use of hydrogels as contraceptives started decades ago, and recent\ndevelopments of nonhormonal hydrogels as contraceptives are promising\nalternatives for both men and women due to the decreased side effects\nwhen compared to currently available hormonal options. In particular,\nthese kinds of nonhormonal options are more appealing to men, as men\nare not as interested in hormonal options as women are.\nThe\ndevelopment of a long-lasting, nonhormonal, completely reversible\ncontraceptive for both men and women would be the most ideal contraceptive\noption. In particular, for men, an option of this kind would allow\nmen to contribute to family planning decisions and the prevention\nof unwanted pregnancies, leveling out the gender inequalities that\nmen currently face in terms of contraceptive options and availability.\nMore nonhormonal, reversible contraceptive options in general would\nallow women to have better reproductive health. Effective family planning\nfor both men and women may lead to a reduction in abortion rates and\ncould enhance maternal and newborn health. Despite the limited publications\nin this growing field, a new hydrogel contraceptive is likely to be\ncommercialized in the near future.\n\nExamples from the literature on hydrogel-based contraceptives were\nsourced from the PubMed NIH database using keywords “hydrogel\ncontraception” searching for the literature published between\n1973 and 2024. Furthermore, the Scopus database using keywords “hydrogel\nAND contraceptive OR contraception” searching for the literature\npublished on any date was also used. Additionally, reference lists\nof relevant papers were used as an additional source of papers.","source_license":"CC-BY-4.0","license_restricted":false}