Polymeric chains crosslinked through supramolecular interactions-directional and reversible non-covalent interactions-compose an emerging class of modular and tunable biomaterials. The choice of chemical moiety utilized in the crosslink affords different thermodynamic and kinetic parameters of association, which in turn illustrate the connectivity and dynamics of the system. These parameters, coupled with the choice of polymeric architecture, can then be engineered to control environmental responsiveness, viscoelasticity, and cargo diffusion profiles, yielding advanced biomaterials which demonstrate rapid shear-thinning, self-healing, and extended release. In this review we examine the relationship between supramolecular crosslink chemistry and biomedically relevant macroscopic properties. We then describe how these properties are currently leveraged in the development of materials for drug delivery, immunology, regenerative medicine, and 3D-bioprinting (253 references).
Sexual function and the effects thereon of testosterone enanthate were studied in six hypogonadal men with the objective of delineating the specific components of male sexuality affected by androgen. To obtain a detailed picture of these components, prospective self-report data (from daily logs) of sexual activity and feelings, recordings of all night penile tumescence, and laboratory psychophysiological data were assessed. Double blind placebo experiments with cross-over design were used to compare the effects of placebo and 200-and 400-mg doses of testosterone enanthate. Erectile responses to erotic film and fantasy were not lower in the hypogonadal patients than in normal men and, in fact, were higher on some parameters, especially prolongation of detumescence time after exposure to film or fantasy. Three subjects who kept consistent daily logs had increased frequencies of sexual acts and feelings, orgasms, and spontaneous erections after testosterone administration. Nocturnal penile tumescence and spontaneous daytime erections were reduced in untreated hypogonadal men and were significantly increased after testosterone treatment, but the laboratory-tested erectile responses to film and fantasy were not affected by testosterone. These data and previous findings lead to the conclusion that the major androgen action on male sexuality involves libido factors {i.e. sexual motivation/interest). Though stimulus-bound erections elicited in the laboratory were not reduced in hypogonadal men, spontaneous (sleep or waking) erections were clearly testosterone dependent. (J Clin Endocrinol Metab 57: 557, 1983) T HOUGH appropriately controlled studies have now clearly vindicated the use of testosterone replacement therapy for the sexual deficits of hypogonadal men, the mechanism of this behavioral action of androgen remains to be established. Recent double blind studies presented self-reported prospective data on sexual activity and libido (1-4) and, also, erections occurring spontaneously (1, 4). However, published data on the effects of androgen on physiological responses to controlled stimuli in the laboratory are still lacking. Such data are important in the elucidation of the mode of action of androgen.One problem in the interpretation of the role of androgen in male sexuality arises from the persistent (albeit poorly documented) reports of the retention of erectile function in castrates (for reviews, see Refs. 5 and 6). These appear to contradict our earlier finding (1) that erections from all causes, including overt sexual behavior, waxed and waned within days of the rise and fall of testosterone levels during periodic administration of testosterone enanthate. The solution may have to do with
In diabetic patients, treatment with insulin and pramlintide (an amylin analogue) is more effective than treatment with insulin only. But because mixtures of insulin and pramlintide are unstable and have to be injected separately, amylin analogues are only used by 1.5% of diabetics needing rapid-acting insulin. Here, we show that the supramolecular modification of insulin and pramlintide with cucurbit[7]uril-conjugated polyethylene glycol improves the pharmacokinetics of the dual-hormone therapy and enhances post-prandial glucagon suppression in diabetic pigs. The co-formulation is stable for over 100 hours at 37 ºC under continuous agitation, whereas commercial formulations of insulin analogues aggregate after 10 hours under similar conditions. In diabetic rats, the administration of the stabilized co-formulation increased the area-of-overlap ratio of the pharmacokinetic curves of pramlintide and insulin to 0.7 ± 0.1 from 0.4 ± 0.2 (mean ± s.d.) for the separate administration of the hormones. The co-administration of supramolecularly stabilized insulin and pramlintide better mimics the endogenous kinetics of co-secreted insulin and amylin, and holds promise as a dual-hormone replacement therapy.
A highly alternating copolymer composed of acrylic acid and styrene (AASTY) is synthesized with controlled radical polymerization by exploiting the reactivity ratios of the monomers to control the monomer sequence. The AASTY copolymers are effective solubilizers of cellular membranes and their embedded proteins, which improves structural characterization by single-particle cryo-electron microscopy (cryo-EM). These copolymers are promising tools for exploring detergent-free membrane protein solubilization and direct formation of native nanodiscs, facilitating structural and functional analysis of the mammalian proteome.
Biofouling on the surface of implanted medical devices and biosensors severely hinders device functionality and drastically shortens device lifetime. Poly(ethylene glycol) and zwitterionic polymers are currently considered “gold‐standard” device coatings to reduce biofouling. To discover novel anti‐biofouling materials, a combinatorial library of polyacrylamide‐based copolymer hydrogels is created, and their ability is screened to prevent fouling from serum and platelet‐rich plasma in a high‐throughput parallel assay. It is found that certain nonintuitive copolymer compositions exhibit superior anti‐biofouling properties over current gold‐standard materials, and machine learning is used to identify key molecular features underpinning their performance. For validation, the surfaces of electrochemical biosensors are coated with hydrogels and their anti‐biofouling performance in vitro and in vivo in rodent models is evaluated. The copolymer hydrogels preserve device function and enable continuous measurements of a small‐molecule drug in vivo better than gold‐standard coatings. The novel methodology described enables the discovery of anti‐biofouling materials that can extend the lifetime of real‐time in vivo sensing devices.
The means by which many herbicides kill susceptible plants are presently unknown (1, 3). Although it is not essential to know the mode of action in order to develop and use a herbicide efficiently, the screening processes by which herbicides are discovered are based upon comparative biochemistry. Se
Biotherapeutics currently dominate the landscape of new drugs because of their exceptional potency and selectivity. Yet, the intricate molecular structures that give rise to these beneficial qualities also render them unstable in formulation. Hydrogels have shown potential as stabilizing excipients for biotherapeutic drugs, providing protection against harsh thermal conditions experienced during distribution and storage. In this work, we report the utilization of a cellulose-based supramolecular hydrogel formed from polymer–nanoparticle (PNP) interactions to encapsulate and stabilize insulin, an important biotherapeutic used widely to treat diabetes. Encapsulation of insulin in these hydrogels prevents insulin aggregation and maintains insulin bioactivity through stressed aging conditions of elevated temperature and continuous agitation for over 28 days. Further, insulin can be easily recovered by dilution of these hydrogels for administration at the point of care. This supramolecular hydrogel system shows promise as a stabilizing excipient to reduce the cold chain dependence of insulin and other biotherapeutics.
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