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Open research questions in Wound Healing and Treatments

49 unresolved questions extracted from the limitations and future-work sections of 521 Wound Healing and Treatments papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • adjunctive therapies Future studies should focus on evaluating long-term outcomes, optimizing the PRP–nanoparticle formulation, and testing the treatment in chronic or infected wound models to enhance clinical applicability. Future studies using infected or delayed-healing models are warranted to further explore the translational potential of these findings.

    Chitosan and chitosan–silver nanoparticles as adjuncts to platelet-rich plasma in canine full-thickness cutaneous wound healing · 2026 · DOI

  • The stability and safety issues of agents in burn wound microbiotherapy are core bottlenecks restricting their application, and establishing a targeted biosafety assessment system has become an urgent priority. In terms of agent stability, factors in the complex burn wound microenvironment including high temperature, pH changes, protease activity, and wound exudate may all inactivate microbiotherapeutic agents, which is one of the key issues facing this therapy. In terms of safety, microbiotherapy has multiple Frontiers in Cellular and Infection Microbiology 14 frontiersin.org Zhang et al. 10.3389/fcimb.2026.1873498 limitations: the use of exogenous microbial agents may trigger host immune reactions. For example, bacteriophages may induce antibody production thus reducing efficacy (Lin et al., 2022; Guo et al., 2024). Some agents may exhibit toxicity to human cells under high doses, especially for large burn wounds with severe infection, excessive doses may lead to cell damage (Rima et al., 2021; Wang et al., 2021; Bucataru and Ciobanasu, 2024). Beyond these general toxicity risks, the application of microbiotherapy faces unique safety challenges. For severely burned patients, the integrity of the skin barrier has been destroyed, and the risk of exogenous live probiotic strains or other active microorganisms entering the blood circulation through the wound has increased significantly, which can easily lead to infections such as bacteremia or sepsis (Hosoda et al., 2025). In addition, the colonization of live bacteria in the wound is difficult to be accurately controlled, and its excessive proliferation may destroy the microecological balance of the wound. Due to the lack of uniform dose and frequency standards, the potential pathogenicity and long-term safety of live bacteria after long-term colonization in vivo are still uncertain, which further increases the complexity of clinical risk management and control (Wang et al., 2025; Zhou and Zhou, 2025). Therefore, the safety evaluation system for in vivo microbiotherapy should not be limited to traditional toxicity tests, and a multi-dimensional monitoring framework covering systematic monitoring, immunogenicity evaluation and long-term colonization tracking must be constructed. Currently, safety evaluations for microbial agents used in burn care lack a standardized framework, unlike vaccines which undergo rigorous Phase I-III trials and long-term follow-up. Given the unique nature of burn treatment, biosafety assessments must establish corresponding protocols (Locker et al., 2024). Specifically, short-term toxicity testing should incorporate doseescalation studies tailored to the characteristics of burn wounds. Immunological safety screening must prioritize evaluating the immunological interactions between the formulation and the host. Long-term monitoring requires tracking subjects for 6 to 12 months to comprehensively assess long-term effects.

    Microbiotherapy: an emerging adjunct for burn wound healing · 2026 · DOI

  • Furthermore, piracetam's ideal therapeutic dosage, mode of administration, length of treatment, and long-term safety profile for wound-healing applications have not yet been determined. Piracetam has been shown to have positive effects on epithelialisation, collagen organization, inflammation, and wound closure in an experimental burn wound investigation [8,10], although there is currently insufficient evidence in VOLUME 10 ISSUE 07 2026 PAGE NO: 21 https://doi.

    REPURPOSING PIRACETAM IN CUTANEOUS WOUND HEALING: MECHANISTIC INSIGHTS INTO OXIDATIVE STRESS, MITOCHONDRIAL FUNCTION AND MICROCIRCULATION · 2026 · DOI

  • Future studies should concentrate on verifying piracetam's ability to cure wounds utilising standardised experimental wound models, such as burn, excision, incision, and diabetic wound models. Mechanistic research assessing piracetam's impact on oxidative stress regulation, mitochondrial function, inflammatory signalling, angiogenesis, collagen deposition, fibroblast proliferation, and PDGF-β-associated cellular responses during tissue repair should receive special attention. Its translational significance in wound care may further be clarified by additional research into topical formulations, localised drug delivery devices, and combination-based therapy approaches. To identify the best therapeutic approach for cutaneous applications, pharmacokinetic and dose-optimization studies are also required. The effectiveness, safety, and therapeutic application of piracetam in acute and chronic wound healing will ultimately need to be established through well planned clinical trials.

    REPURPOSING PIRACETAM IN CUTANEOUS WOUND HEALING: MECHANISTIC INSIGHTS INTO OXIDATIVE STRESS, MITOCHONDRIAL FUNCTION AND MICROCIRCULATION · 2026 · DOI

  • These findings suggest the potential of the formulated gels as alternative topical agents under alcohol- impaired further investigation is required to confirm their efficacy and to clarify the mechanisms involved. conditions, although Considering the limitations of the present study, including the small sample size, absence of a vehicle-only gel base histological control, evaluation, and limited 30-day observation period, future studies are recommended to endpoint-only \ 16 the formulated further validate the wound-healing potential of gels.

    Wound Healing Activity of Formulated NipaAlco Gel on Chronic-Binge Ethanol-Fed Male ICR Mice (Mus musculus L.) · 2026 · DOI

  • Up to now, most of the research on Twist1 has focused on the field of tumors, and there have been no reports on its involvement in wound healing or reg- ulation of EMT in keratinocytes.

    The role and mechanism by which micropeptide WHPP promote refractory wound healing · 2026 · DOI

  • Probiotics and their metabolites have been shown to modulate inflammation and promote tissue repair; however, the therapeutic potential of probiotic‐derived cell-free supernatants (CFS) for skin wound healing remains underexplored.

    Cell-free Supernatant From Lactobacillus Casei KE-99 Promotes Skin Wound Healing · 2026 · DOI

  • While the proposed self-healing smart bandage demonstrates strong computational and AI-driven performance, several research directions remain essential for translating this con- cept into practical clinical use. The most crucial next step involves in-vivo testing to validate the device’s biocompat- ibility, long-term stability, and sensing reliability under real physiological conditions. Although simulation outcomes strongly support the feasibility of the design, biological environments introduce additional complexities such as enzyme-mediated degradation, immune response, variable wound exudate composition, and mechanical stresses arising from patient mobility. Controlled in-vivo studies on animal models will therefore be critical for assessing wound-tissue interactions, confirming sensor performance, and quantify- ing healing outcomes compared to standard wound-care approaches [47, 48]. Future work will focus on integrating image-based wound analysis with sensor data to develop a fully multimodal AI framework combining temporal and spatial features. Another promising direction is the integration of wireless power delivery mechanisms. The present design relies on low-power electronics supported by local batteries or pas- sive NFC-based interrogation. Incorporating wireless power transfer modules—such as inductive coupling, resonant wireless power coils, or thin-film energy harvesters—would enable continuous, battery-free operation, thereby enhanc- ing wearability and long-term usability. Wireless power sys- tems would also allow the smart bandage to support more advanced sensing circuits, onboard data storage, and haptic- feedback mechanisms without compromising form factor or flexibility [49, 50]. The device can be further enhanced by incorporating drug-delivery capabilities directly into the multilayer struc- ture. Embedding micro-reservoirs loaded with antimicro- bial agents, growth factors, or anti-inflammatory molecules, combined with controlled release triggered by temperature, pH, or electrical stimulation, would allow the bandage not only to monitor healing but also to respond therapeutically [51]. Self-healing hydrogels are excellent candidates for encapsulating these drug carriers, and integrating micro- fluidic pathways or hydrogel swelling-based valves would enable precise, on-demand medication release. Lastly, future versions of the smart bandage may ben- efit from soft robotics–based wound compression and actuation. Wound healing, especially for chronic ulcers, is often improved through controlled pressure, mechanical stimulation, and enhanced blood circulation. Integrating soft pneumatic actuators, dielectric elastomer muscles, or shape-memory polymer elements could enable dynamic compression tailored to wound states identified by the AI model [52, 53]. This would transform the bandage from a passive monitoring device into an active therapeutic system capable of personalized mechanical intervention. Collectively, these future directions outline a pathway toward developing a fully autonomous, multifunctional, and clinically transformative smart-bandage platform that integrates diagnostics, analytics, and therapy into a single wearable system.

    Self-healing 2D material composites for intelligent smart bandages: Multiphysics simulation and AI-enabled wound assessment · 2026 · DOI

  • positive findings may overrepresent therapeutic ben- efits. Also, the scalability, regulatory considerations, and cost-effectiveness of advanced curcumin formu- lations remain insufficiently explored, warranting further research to support clinical translation. Acknowledgements We sincerely acknowledge and thank the respective universities and institutes for providing the necessary facilities and support for the completion of this review article. No funding or grant was received. Author contributions Conceptualization: Goutam Thakur; Writing—original draft preparation: Debalina Bose; Writing— review & editing: Goutam Thakur, Debalina Bose, Chinthana Chidanand All the authors have read and approved the final manuscript. Funding Open access funding provided by Manipal Academy of Higher Education, Manipal.

    From phytochemistry to biomaterials: curcumin-based scaffolds in wound management · 2026 · DOI

  • The paper does not specify whether pH/ROS-responsive smart hydrogels have been tested for compatibility with standard chronic wound care protocols, including concurrent antibiotic therapy, negative pressure wound therapy, or enzymatic debridement agents, which is necessary before transitioning from passive dressing replacement to pathology-guided intervention.

    pH/ROS-responsive smart hydrogels for infection control and immune microenvironment modulation in chronic wound healing · 2026 · DOI

  • The excerpt does not address comparative long-term biocompatibility and degradation kinetics of pH/ROS-responsive hydrogels in chronic diabetic versus non-diabetic wound models, which is essential for determining whether immune modulation efficacy differs based on the underlying pathological microenvironment.

    pH/ROS-responsive smart hydrogels for infection control and immune microenvironment modulation in chronic wound healing · 2026 · DOI

  • The paper emphasizes macrophage-centered immune microenvironment modulation but lacks specific characterization of how different pH ranges (acidic vs. neutral chronic wound pH) and ROS concentrations dynamically modulate M1/M2 macrophage polarization kinetics and phenotype switching during the healing cascade in pH/ROS-responsive hydrogels.

    pH/ROS-responsive smart hydrogels for infection control and immune microenvironment modulation in chronic wound healing · 2026 · DOI

  • The paper identifies biosafety, manufacturability, and translational validation as critical barriers for pH/ROS-responsive smart hydrogels in chronic wound care, but does not specify standardized biocompatibility testing protocols, sterilization methods, or scale-up production pathways needed to move these biomaterials from laboratory synthesis to clinical-grade dressing formulations.

    pH/ROS-responsive smart hydrogels for infection control and immune microenvironment modulation in chronic wound healing · 2026 · DOI

  • chronic inflammation, Diabetic wounds represent one of the most challenging manifestations of metabolic disease, arising from the convergence of impaired angiogenesis, oxidative stress, neuropathy, infection and extracellular matrix dysfunction. Traditional therapeutic strategies-largely focused on symptom management or single-target interventions—have proven insufficient to address the multifactorial and dynamic nature of these wounds. As synthesized this review, nanocarrier-mediated drug delivery systems offer a spatially, transformative paradigm by temporally therapeutic intervention. and molecularly precise throughout enabling 10.1 Key Advances Highlighted in This Review This review highlights several transformative advances that are redefining the management of diabetic wounds. Nanocarrier platforms have shifted the therapeutic paradigm from single-agent interventions to systemslevel approaches, integrating herbal, synthetic, semisynthetic and gene-based therapeutics to simultaneously modulate inflammation, angiogenesis, infection and tissue regeneration. Modern nanomaterials contribute beyond passive delivery by actively shaping wound biology through intrinsic antimicrobial activity, redox modulation, immune regulation and support of extracellular matrix remodeling. At the molecular level, gene-based payloads, miRNAs, and siRNAs delivered via non-viral nanocarriers offer precise control over dysregulated signaling networks, enabling pathway addressing reprogramming downstream deficits. Importantly, emerging strategies emphasize the heterogeneity of diabetic wounds, advocating for disorder-specific and phase-aware designs that tailor interventions to wound subtype and healing stage, thereby maximizing therapeutic efficacy and advancing personalized regenerative medicine.

    Smart Nanocarrier Systems for Diabetic Wound Healing: Preclinical Innovations and Clinical Progress in Drug and Gene Delivery · 2026 · DOI

  • Advances in smart wound dressings, AI-assisted formulation design and personalized medicine are expected to accelerate clinical translation of nanocarrierbased therapies.169 Integration of nanocarriers with wearable sensors and stimuli-responsive biomaterials represents a promising frontier for adaptive, real-time wound management. Collectively, the convergence of insight, material mechanistic and translational rigor positions nanocarrier-mediated therapies as a transformative approach for diabetic wound care. The following section synthesizes key insights and future perspectives.

    Smart Nanocarrier Systems for Diabetic Wound Healing: Preclinical Innovations and Clinical Progress in Drug and Gene Delivery · 2026 · DOI

  • Although oxidative stress and mechanical scratching can aggravate AD inflammation, treatment targeting scratching is often overlooked, and the efficiency of mechano-chemically synergistic therapy remains unclear.

    Hydrogel dressing integrating FAK inhibition and ROS scavenging for mechano-chemical treatment of atopic dermatitis · 2023 · DOI

  • To the best of our knowledge, the effect of miconazole and terbinafine on HaCaT cells has not been studied with respect to intracellular ROS stimulation.

    Miconazole and terbinafine induced reactive oxygen species accumulation and topical toxicity in human keratinocytes · 2020 · DOI

  • Autologous cutis and subcutis micrografts and collagen–elastin dermal scaffolds have each shown promise in wound healing, but their combination has not been previously investigated in a clinical study.

    Autologous cutis and subcutis micrografts combined with a collagen–elastin dermal scaffold for chronic wounds: a retrospective single-arm clinical study with prospectively collected data · 2026 · DOI

  • In the oral context, hyaluronic acid-based adjunctive therapies have shown promise in improving early post-extraction healing in diabetes; however, clinical evidence remains limited.

    Healing Response to Hyaluronic Acid Supplemented with Selected Amino Acids: A Pooled Analysis of Two Clinical Studies · 2026 · DOI

  • Future research will focus on scal- ing up the production process and initiating clinical trials to thoroughly evaluate the safety and efficacy of the developed membrane.

    Improving wound dressing applications of the fabricated bacterial cellulose membrane incorporated hyaluronic acid and marine collagen · 2026 · DOI

  • However, the use of Echinacea as a wound dressing has not been adequately investigated, and its specific mechanism for promoting wound healing has not been fully elucidated.

    Preclinical model of Echinacea-functionalized silk fibroin–chitosan transparent membranes with enhanced hair follicle regeneration and antibacterial properties for wound healing · 2026 · DOI

  • faecium , particularly vancomycin-resistant strains, is an understudied, clinically important cause of chronic diabetic wound infections.

    <i>Enterococcus faecium</i> colonization and persistence in a model of diabetic wound infection · 2026 · DOI

  • Balancing the initial pro-inflammatory response with debris removal and tissue rebuilding remains elusive in most cases, leading to pain, drastic quality-of-life deterioration, and, eventually, amputation.

    Human Amniotic Membrane Dressing as a Non-Surgical Alternative for Extensive Chronic Ulcers: A Comparative Case Study · 2026 · DOI

  • The study evaluated hydrogel cytocompatibility using only human dermal fibroblast cells; testing with additional cell types relevant to the target application would strengthen biocompatibility assessment.

    Dynamic OP–Gel–PVP Hydrogels with Tunable Network Properties for Injectable, Self-Healing, and Adhesive Biomaterial Applications · 2026 · DOI

  • The delayed mucosal healing of tooth extraction sockets in diabetes has few known effective treatment strategies, and its underlying mechanism remains unknown.

    Detection of senescent cells in the mucosal healing process on type 2 diabetic rats after tooth extraction for biomaterial development · 2024 · DOI

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49 open questions have been extracted from the limitations and future-work passages of 521 Wound Healing and Treatments papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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