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Direct reciprocity is one of the key mechanisms accounting for cooperation in our social life. According to recent understanding, most of classical strategies for direct reciprocity fall into one of two classes, ‘partners’ or ‘rivals’. A ‘partner’ is a generous strategy achieving mutual cooperation, and a ‘rival’ never lets the co-player become better off. They have different working conditions: For example, partners show good performance in a large population, whereas rivals do in head-to-head matches. By means of exhaustive enumeration, we demonstrate the existence of strategies that act as both partners and rivals. Among them, we focus on a human-interpretable strategy, named ‘CAPRI’ after its five characteristic ingredients, i.e., cooperate, accept, punish, recover, and defect otherwise. Our evolutionary simulation shows excellent performance of CAPRI in a broad range of environmental conditions.

In a social dilemma, cooperation is collectively optimal, yet individually each group member prefers to defect. A class of successful strategies of direct reciprocity were recently found for the iterated prisoner’s dilemma and for the iterated three-person public-goods game: By a successful strategy, we mean that it constitutes a cooperative Nash equilibrium under implementation error, with assuring that the long-term payoff never becomes less than the co-players’ regardless of their strategies, when the error rate is small. Although we have a list of actions prescribed by each successful strategy, the rationale behind them has not been fully understood for the iterated public-goods game because the list has hundreds of entries to deal with every relevant history of previous interactions. In this paper, we propose a method to convert such history-based representation into an automaton with a minimal number of states. Our main finding is that a successful strategy for the iterated three-person public-goods game can be represented as a 10-state automaton by this method. In this automaton, each state can be interpreted as the player’s internal judgement of the situation, such as trustworthiness of the co-players and the need to redeem oneself after defection. This result thus suggests a comprehensible way to choose an appropriate action at each step towards cooperation based on a situational judgement, which is mapped from the history of interactions.

In this study we present polymeric microneedles composed of multiple layers to control drug release kinetics. Layered microneedles were fabricated by spraying poly(lactic-co-glycolic acid) (PLGA) and polyvinylpyrrolidone (PVP) in sequence, and were characterized by mechanical testing and ex vivo skin insertion tests. The compression test demonstrated that no noticeable layer separation occurred, indicating good adhesion between PLGA and PVP layers. Histological examination confirmed that the microneedles were successfully inserted into the skin and indicated biphasic release of dyes incorporated within microneedle matrices. Structural changes of a model protein drug, bovine serum albumin (BSA), in PLGA and PVP matrices were examined by circular dichroism (CD) and fluorescence spectroscopy. The results showed that the tertiary structure of BSA was well maintained in both PLGA and PVP layers while the secondary structures were slightly changed during microneedle fabrication. In vitro release studies showed that over 60% of BSA in the PLGA layer was released within 1 h, followed by continuous slow release over the course of the experiments (7 days), while BSA in the PVP layer was completely released within 0.5 h. The initial burst of BSA from PLGA was further controlled by depositing a blank PLGA layer prior to forming the PLGA layer containing BSA. The blank PLGA layer acted as a diffusion barrier, resulting in a reduced initial burst. The formation of the PLGA diffusion barrier was visualized using confocal microscopy. Our results suggest that the spray-formed multilayer microneedles could be an attractive transdermal drug delivery system that is capable of modulating a drug release profile.

L-HBsAg is a third-generation hepatitis vaccine capable of inducing antibodies in non-responders and thus providing potentially therapeutic treatment. In this study, L-HBsAg was administered using microneedles (MN) without an adjuvant to induce intradermal (ID) immunization, and the efficacy of ID immunization was compared with that of intramuscular (IM) immunization that uses a conventional formulation with an adjuvant of aluminum hydroxide (L-HBsAg-AL-IM). The L-HBsAg was dip-coated onto 800-μm-long microneedles made of polylactic acid (PLA). Delivery efficiency and administration time were determined through in vitro experiments using porcine skin. The denaturation of the formulation against sterilization by gamma rays was observed. A storage test and a freeze-thaw cycle test of the microneedles with trehalose as a stabilizer (L-HBsAg-MN-Tre) were observed. An antibody titer of L-HBsAg-MN-Tre was compared with that of the conventional IM immunization of the L-HBsAg solution with aluminum hydroxide (L-HBsAg-AL-IM). The formulation containing L-HBsAg was located on the upper third of the microneedle tips. The formulation on the MN was dissolved and delivered within 30 min of insertion into porcine skin in vitro. Trehalose was selected as a stabilizer, and the stabilizing effect increased with the increase of trehalose content in the solidified formulation. L-HBsAg-MN with 15% of trehalose was stable for 7 days at 40 °C and showed increased stability compared to the conventional liquid formulations. L-HBsAg-MN-Tre showed improved stability during the freeze-thaw cycle. The antibody titer of L-HBsAg-MN-Tre at 28 days was higher than that of L-HBsAg-AL-IM. ID administration of L-HBsAg-MN-Tre showed better efficacy and improved thermal and freeze thaw stability compared to L-HBsAg-AL-IM. Therefore, L-HBsAg-MN-Tre administration showed the possibility of ID delivery of L-HBsAg without the use of an adjuvant for the efficacy, convenience, and safety of pediatric vaccination.

Although smallpox has been eradicated globally, the potential use of the smallpox virus in bioterrorism indicates the importance of stockpiling smallpox vaccines. Considering the advantages of microneedle-based vaccination over conventional needle injections, in this study, we examined the feasibility of microneedle-based smallpox vaccination as an alternative approach for stockpiling smallpox vaccines. We prepared polylactic acid (PLA) microneedle array patches by micromolding and loaded a second-generation smallpox vaccine on the microneedle tips via dip coating. We evaluated the effect of excipients and drying conditions on vaccine stability in vitro and examined immune responses in female BALB/c mice by measuring neutralizing antibodies and interferon (IFN)-γ-secreting cells. Approximately 40% of the virus titer was reduced during the vaccine-coating process, with or without excipients. At −20 °C, the smallpox vaccine coated on the microneedles was stable up to 6 months. Compared to natural evaporation, vacuum drying was more efficient in improving the smallpox vaccine stability. Microneedle-based vaccination of the mice elicited neutralizing antibodies beginning 3 weeks after immunization; the levels were maintained for 12 weeks. It significantly increased IFN-γ-secreting cells 12 weeks after priming, indicating the induction of cellular immune responses. The smallpox-vaccine-coated microneedles could serve as an alternative delivery system for vaccination and stockpiling.

PurposeEpicutaneous immunotherapy (EPIT) is being studied as a method for treating allergic rhinitis because of skin immunology, user convenience and enhanced patient compliance. However, the use of EPIT is limited because of the very low skin permeability of the allergen. In this study, the limitations of EPIT were overcome by using sophisticated delivery with microneedles. The immunological efficacy of this method was studied in a murine model of house dust mite (HDM) allergic rhinitis.MethodsThe length of the microneedles was 400 μm, and the coating formulation containing HDM was locally distributed near the end of the microneedle tips. The change of distribution of FITC-dextran in porcine skin in vitro was observed over time using a confocal microscope. The effect of immunotherapy in the allergic rhinitis model, sensitized by HDM-coated microneedles (HDM MNs), was observed according to the amount of HDM applied.ResultsThe microneedles delivered the coating formulation with precision into the porcine skin layer, and the coated formulation on the microneedles was all dissolved in the porcine skin in vitro within 20 min of administration and then gradually diffused into the skin layer. When HDM MNs were administered to mice, a 0.1-μg dose of HDM provided the most effective immunization, and improved efficacy was shown between 0.1- and 0.5- μg doses of HDM.ConclusionsEffective immunotherapy can be achieved by precision delivery of the allergen into the skin layer, and microneedles can provide effective immunological therapy by delivering the appropriate amount of allergen.

In this study we present the fabrication of multilayer microneedles with circular obelisk and beveled-circular obelisk geometries, which have potential applications in implantable drug delivery devices. Micro-milling was adopted as an environmental-friendly and cost-effective way to fabricate primary metal microneedle masters. Polylactic acid (PLA) microneedles with sharp tips were then obtained by micromolding followed by oxygen plasma etching and used for preparing polydimethylsiloxane (PDMS) microneedle molds. A spray deposition process was employed for microneedle fabrication to facilitate the formation of multilayer microneedles while helping in maintenance of drug stability. Multilayer microneedles were successfully formed by sequential spraying of poly(lactic-co-glycolic acid) (PLGA) and polyvinylpyrrolidone (PVP) solutions into the mold. The fabricated PLGA-PVP multilayer microneedles penetrated the pig cadaver skin without breakage and released dyes in the skin at different rates, which reveals the potential for implantable microneedles enabling controlled release. Mechanical testing demonstrated that the obelisk-shaped microneedles were mechanically stronger than a pyramid-shaped microneedle and suggested that strong adhesion between PLGA and PVP layers was achieved as well. Structural stability and functionality of a model drug, horseradish peroxidase (HRP), upon spray deposition was examined using circular dichroism (CD) spectroscopy and enzyme activity assay. HRP retained its secondary structure and activity in PVP, whereas HRP in PLGA showed structural changes and reduced activity. Combination of micro-milling and spray deposition would be an attractive way of fabricating drug-containing polymer microneedles with various geometries while reducing prototyping time and process-induced drug instability.

People tend to have their social interactions with members of their own community. Such group-structured interactions can have a profound impact on the behaviors that evolve. Group structure affects the way people cooperate, and how they reciprocate each other’s cooperative actions. Past work has shown that population structure and reciprocity can both promote the evolution of cooperation. Yet the impact of these mechanisms has been typically studied in isolation. In this work, we study how the two mechanisms interact. Using a game-theoretic model, we explore how people engage in reciprocal cooperation in group-structured populations, compared to well-mixed populations of equal size. In this model, the population is subdivided into groups. Individuals engage in pairwise interactions within groups while they also have chances to imitate strategies outside the groups. To derive analytical results, we focus on two scenarios. In the first scenario, we assume a complete separation of time scales. Mutations are rare compared to between-group comparisons, which themselves are rare compared to within-group comparisons. In the second scenario, there is a partial separation of time scales, where mutations and between-group comparisons occur at a comparable rate. In both scenarios, we find that the effect of population structure depends on the benefit of cooperation. When this benefit is small, group-structured populations are more cooperative. But when the benefit is large, well-mixed populations result in more cooperation. Overall, our results reveal how group structure can sometimes enhance and sometimes suppress the evolution of cooperation.

Reputation is a powerful mechanism to enforce cooperation among unrelated individuals through indirect reciprocity, but it suffers from disagreement originating from private assessment, noise, and incomplete information. In this work, we investigate stability of cooperation in the donation game by regarding each player’s reputation and behaviour as continuous variables. Through perturbative calculation, we derive a condition that a social norm should satisfy to give penalties to its close variants, provided that everyone initially cooperates with a good reputation, and this result is supported by numerical simulation. A crucial factor of the condition is whether a well-reputed player’s donation to an ill-reputed co-player is appreciated by other members of the society, and the condition can be reduced to a threshold for the benefit-cost ratio of cooperation which depends on the reputational sensitivity to a donor’s behaviour as well as on the behavioural sensitivity to a recipient’s reputation. Our continuum formulation suggests how indirect reciprocity can work beyond the dichotomy between good and bad even in the presence of inhomogeneity, noise, and incomplete information.

Background and objectives: The development of a five-in-one vaccine microneedle patch (five-in-one MN patch) aims to address challenges in administering vaccines against Diphtheria (DT), Tetanus (TT), Pertussis (wP), Hepatitis B (HBsAg), and Haemophilus influenzae type b (Hib). Combining multiple vaccines into a single patch offers a novel solution to improve vaccine accessibility, stability, and delivery efficiency, particularly in resource-limited settings. Methods: The five-in-one MN patch consists of four distinct microneedle arrays: DT and TT vaccines are coated together on one array, while wP, HepB, and Hib vaccines are coated separately on individual arrays. The patch was tested for long-term stability (12 months at 25 °C) and evaluated for immunogenicity in mice and minipigs. Antibody titers were measured using ELISA to compare immune responses between microneedle-based delivery and traditional intramuscular (IM) injection. Results: The five-in-one MN patch demonstrated stable antigenicity for up to 12 months at room temperature. In animal studies, the patch induced antibody titers comparable to traditional IM injections for all vaccines. Notably, immunogenic responses to Pertussis and Haemophilus influenzae type b vaccines via microneedles were reported for the first time. The patch facilitated the simultaneous yet independent delivery of vaccines, preserving their immunogenicity without interference. Conclusions: The five-in-one MN patch represents a significant advancement in vaccine delivery by enabling stable, minimally invasive, and efficient immunization. Its innovative design addresses the critical limitations of combination vaccines and has the potential to enhance vaccine accessibility in low- and middle-income countries. Future studies will focus on optimizing patch application techniques and evaluating broader clinical applicability.