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Importance of Pursuing Self-Healing Hydrogels To Address Wound Healing 

Abstract

Wound healing is an integral part of human health and maintaining homeostasis, although generally healing resolves within 8-12 weeks for acute wounds, chronic wounds may extend years into the future for various reasons (Amara, et al. 2025). The typical wound heals in four major stages through the initial impediment of blood flow, inflammation to clear microbes, new blood vessel development along with fibroblast proliferation, followed by a gradual contracting of the wound. Currently chronic wounds are difficult to treat and medical procedures commonly used to administer open wounds either induce secondary injuries or lack properties to ensure wound closure. In the past decade, extensive research into hydrogel production that improves wound healing have been conducted with some hydrogels created having anti-microbial properties, strong adhesion, great water retention, or even self-healing. More studies must be conducted for human trials to fully quantify the efficacy of these hydrogels, however the data shows promising results. The literature has shown carbon nanotubes along with 3d printed biomaterials accelerated wound contraction greatly and could be used more to facilitate skin reconstruction, (Ehsaniford, et al. 2025) this field can be quite promising especially for those suffering from chronic wound healing. In a recent study by (Amara, et al. 2025), it further shows how silver nanoparticles that are embedded into the 3D printed hydrogel patch directly are strong against bacterial activity by E. coli and also S. aureus. In this review paper we propose a 3D-printed hydrogel that has silver nanoparticles embedded inside its structure along with the addition of an in-built drug delivery system to reduce oxidative stress and microbial activity whilst upregulating genes responsible for tissue regeneration.

Introduction

The maintenance of homeostasis is important for the human body to remain in a stable state for regular cellular function, injury especially wounds disrupt homeostasis & their ability to be resolved provides a snapshot of the person’s health. Skin serves as an external barrier against the environment and the pathogens present from penetrating into the body, when this barrier is damaged the body is vulnerable to the environment, in some cases tissue damage and death occurs. The process of wound healing allows the body to repair damaged blood vessels & tissue at best, or create a fibrous layer to quickly seal the wound site. In extreme cases however, the wound created is too large or located along an artery or vein, rapid blood loss in this case leads to death before platelets can sufficiently restrict blood flow. For these cases medical procedures with varying effects have been utilized to stem blood flow and protect the wound, in contemporary society biomaterials are designed by major corporations and government entities for this purpose. Biomaterials must be biocompatible to preclude adverse reactions, along a dynamic wound site all criteria of biocompatibility including toxicology, extrinsic organisms, mechanical effects, and the cell response affect the material’s ability to help seal the wound. Improper mechanical considerations have produced materials that cause secondary injury, materials that corrode in the in-vivo environment (usually metals) may create oxidative stress or toxicity not including endotoxins produced by microbes on the material. The molecular structure of the polymers composing the biomaterial also need to selectively react with proteins in the bloodstream that do not elicit an immune response, otherwise wound healing will be prioritized into isolating the implant instead of regeneration. Biomaterials that pass that criteria are generally suitable for use, however they should maintain properties that enhance wound healing instead of simply not exacerbating the inflammation response. 

Wound Healing Process and Complications

The process of wound healing contains multiple steps with specific cell functions to repair contract the wound site & regenerate tissue. Hemostasis is the first step of wound healing, intact blood vessels begin to secrete blood coagulants while the damaged vessel constricts as fibrin & thrombin production increases.  Platelets aggregate to seal the damaged blood vessel wall before a fibrin clot forms to stop blood flow, after this step inflammation occurs as neutrophils and macrophages are recruited to the wound site. Bacteria or other microorganisms may enter the wound site during injury, neutrophils act to clear these microbes from the wound as the macrophages phagocytose bacteria. Growth factors that enable the growth, migration, and proliferation of fibroblasts along the wound site are secreted by both neutrophils and macrophages toward the end of the healing process. The inflammation stage is the most common period where wound healing stagnates and becomes chronic due to necrosis, infections, pain, and excessive leakage from blood vessels (Amara, et al. 2025). In the proliferation stage of wound healing, fibroblasts proliferate rapidly across the wound site as angiogenesis induced by endothelial cells creates new blood cells directed toward the injury allowing efficient cell migration. Remodeling finalizes wound healing as fibroblasts produce large amounts of type I collagen while contracting the wound through their contractile actin gene expression.

Skin healing is a multifaceted process between extracellular signals and cellular responses, the rate and ability of skin to heal is a generally good indicator of one’s health. Chronic wounds may lead to complications that lead to amputations, increased mortality risk, lower life quality, due to infections, impaired angiogenesis and cellular dysfunction. In addition certain conditions including diabetes impair cell function, hyperglycemia is a common trait of diabetics, the high glucose levels produce oxygen free radicals that lead to oxidative stress, surrounding tissue is damaged which reduces the ability of cells to replicate. In effect a feedback loop occurs especially if an infection of the wound site occurs, oxidative stress prevents cell replication & damages tissues which prolongs healing allowing bacteria or other microorganisms to infiltrate the exposed wound site. Without treatment, diabetics are at higher risk for chronic wound complications which can potentially be fatal. (Samarawickrama, et al 2025) mentioned specifically Diabetic foot ulcer mice contained a much higher concentration of SenMayo genes than their non-DFU counterparts, more of their upregulated genes were regulated toward cytokine production, immune cell differentiation, and chemotaxis, compared to cell-proliferation, chromosome segregation, organelle fission & mitotic cell cycle phase transitions. The stagnation of healing in the inflammation stage is one major reason chronic wounds cannot heal regularly, medical advancements are now beginning to account for this fact. 

Shortfalls of Common Medical Procedures:

The average person typically has access to various treatments that are satisfactory solutions for minor injuries, during surgery stitches, sutures, and staples all successfully close wounds. However many of these methods do not provide the wounds protection, moisture retention, or prevent infections by themselves which is relevant especially in unsterile environments and wounds directly exposed to air. The WVTR of healthy skin is around 204 g/m2 per day, while for wounded skin it ranges depending on the injury. For example, for a first-degree burn, the WVTR is 279 g/m2 per day, and for a granulating wound 5138 g/m2 per day(Amara, et al, para 3.3, 2025). To alleviate excessive moisture evaporation from open wounds, hydrogels have great water retention properties and have proven effective for aiding wound healing.  Most hydrogels however lack the anti-microbial properties necessary to ensure wounds heal, infections require a substantial immune response to combat with the resulting damage from both the pathogens & immune system leading to tissue damage. Additional concerns from modern hydrogel fabrication relating to poor flexibility of size or improper mechanical properties for the specific wound site are halting widespread adoption. 3D printing may show fruition as specific material concentrations can be input and modeled with exact specifications from a computer program. Materials that deform at higher temperatures, produce reactions, etc pose a significant issue as 3D printers have a limited range of operating conditions, either the material or 3D printer could become damaged in this scenario.

Promising Hydrogel Solutions

Numerous hydrogels have been developed that address the microbial burden, water retention, and wound sealing problems common of most medical procedures. A FLA@ZIF-8/KC@KGM hydrogel scaffold with 98.9% water content, hydrophilic contact angle of 22.8 degrees, and could carry FLA with enhanced drug delivery at acidic PH levels was produced by researchers in (Yu, et al. 2024) and was quite promising. This hydrogel contained kappa-carrageenan as well as konjac glucomannan within its structure, KC was chosen for its rapid gelation time, strong adhesion, and drug delivery capabilities while KGM increased water retention through its high water absorbance, antibacterial properties, and fibroblast proliferation in its presence. As mentioned in the wound healing section of this review fibroblast proliferation is an important step before the wound can be successfully contracted. The antibacterial properties, adhesion, and water retention of this hydrogel also serve three major purposes of preventing dehydration, allowing wound contraction while providing a physical barrier, and keeping bacteria out the wound site. Less time in the inflammation stage is required to transition to the fibroblast proliferation and remodeling stages especially due to the lack of bacterial intrusion. Addition of silver nanoparticles up to the 10% concentration enabled accelerated wound healing past day 9 in the rats examined while also increasing the tensile strength to 1.15MPA (Yu, et al 2024). One potential issue could be the cytotoxicity of excess silver especially as the hydrogel degrades.

Figure of the FLA@ZIF-8/KC@KGM hydrogels at differing silver nanoparticle concentrations

Some hydrogels are able to conduct self repair due to crosslinking bonds within their structure, even if the hydrogel is split upon external forces, a combination of covalent bonds & Van der Waals forces allow these hydrogels to reassemble similar to DNA’s reassembly. Self healing hydrogels have shown promise for wound healing due to the number of forces acting upon the wound site, a person may stretch, compress, or twist the injury which may degrade the wound dressing. A HA hydrogel developed in Ren’s study (2023) had successfully gelated within 1-2 minutes, aggregate red blood cells and platelets inside its hydrogel network, resist tension, compressive, shear forces, and water when bonded to porcine, and could seal wounds within 2 minutes. The capabilities of this hydrogel made it quite successful in sealing off wounds both internally and externally efficiently as hydrazide linkages between the OPA and hydrazide allowed continuous reformation. Wounds located along joints or near major blood vessels would benefit most from this hydrogel as the strong adhesive would resist external force while also allowing the fibroblasts in the wound site to quickly remodel the ecm. An untreated wound takes significantly longer to heal under these conditions, scarring would likely be preferred by the body to save time repairing these regions without the hydrogel as the risk of infection / internal damage without a barrier is too great. As for concerns regarding degradation the addition of di-sulfide bonds allowed a more controlled degradation of the hydrogel, without the presence of hyaluronidase this HA-Peg hydrogel degraded over 40 days (Ren, et al. 2023).

Carbon nanotube hydrogels are another field of interest as their structure is anti-bacterial, can be used to buttress other polymers, and become a great scaffold for cells to adhere and proliferate from. A specific conformation of chitosan, linalool, and carbon nanotubes combined to protect the linalool for drug delivery performed very well in wound contraction and healing. According to Ehsaniford’s study in 2025; The enhanced wound healing observed with CS/SW/L4 hydrogels may be attributed to several mechanisms: chitosan promotes hemostasis and tissue regeneration; single-walled carbon nanotubes support cellular adhesion and scaffold formation; and linalool exerts anti-inflammatory, antioxidant, and pro-apoptotic effects that reduce bacterial burden and oxidative stress, thereby accelerating tissue repair (para ‘Wound contraction and total bacterial count levels’). Apoptosis is controlled self death, although it may appear counterintuitive, apoptosis is important to clear the wound site for remodelling & new tissue regeneration. With the damaged cells removed from the wound site & a lack of oxidative stress, wound healing can progress without additional impediments. The addition of the carbon nanotube as a scaffold also allows cells to easily adhere and regenerate in the wound site, without this scaffold the regeneration process is much slower as there is no pre-existing surface to adhere to for incoming cells. In fact this Chitosan-Carbon nanotube hydrogel in combination with linalool increased the gene expression of SOD and GPx in the wound sites of the mice injected with the hydrogel, these two genes are responsible for new skin development which could be promising for human trials if new skin instead of fibrosis is predominant. (Ehsaniford, et al. 2025) 

The above figure shows the efficacy of the CS/SWCNT hydrogel at preventing oxidative stress, linalool’s presence improves the anti-oxidant properties of the hydrogel, however even the base hydrogel without linalool is more equipped to control oxidative stress relative to the control group. 

With the structures of chitosan and carbon nanotubes additionally disrupting the cell membrane of bacteria, this hydrogel is effective at keeping the wound site sterile. Importantly the risk of accidental oxidative stress is miniscule as there is no metal present to react within the body to produce oxygen free radicals.

Proposal

Based on recent medical advances and the literature noted above, I believe the best self healing hydrogel for the majority of wounds is likely a mix of 3D printed HA-PEG material along with 10% concentration of silver nanoparticle, and a conjugate between KGM and the CS/SWCNT hydrogel listed in the previous section. KGM provides the necessary water retention needed to keep the wound moist as that allows cells to proliferate, the HA-PEG provides the adhesive strength and reassembly needed for wounds around joints or ligaments. For the anti-microbial properties the chitosan, carbon nanotubes, silver nanoparticles, and KGM will serve to disrupt the bacterial cell membrane or prevent replication of other microorganisms, whether this can be applied to an infected wound would need further testing. If infected wound applications can occur, the drug delivery system built into the carbon nanotubes can be utilized to administer the necessary medicine to the affected wound at a controlled pace. In situations that require long-term application of a drug, the hydrogel structure through 3D printing or reduction of the concentration for some molecules may be necessary.

This hydrogel has several challenges into producing and maintaining its structure, most notably the presence of silver nanoparticles during degradation could interfere with the self-healing aspect of the HA-PEG portion of this hydrogel or leach into surrounding tissue which can be cytotoxic. Additionally, the reactivity of each compound with one another may alter the hydrogel into an unusable form when inserted in-vivo or during the 3D printing process which requires high temperatures during the printing process. A final major consideration includes the hydrogel’s degradation, as the wound heals some components will degrade at different rates leaving a risk for injury or a foreign body reaction if a negative cell-interaction occurs. While the base compounds are biocompatible, reactions within the in-vivo environment over an extended period could be a cause for concern if new inflammation arises.

Conclusion

Self-healing hydrogels with high moisture retention, adhesion, and antimicrobial properties are potentially a future conventional method of wound healing. What is still unclear is how effective these hydrogels will be within human trials, their feasibility, and any long term effects that may arise especially for those used to treat chronic wounds. A potential hydrogel that includes ABT 263 for diabetic patients might be a promising venture due to it’s clearing of cell senescence in chronic wounds allowing healing to resume (Samarawickrama, et al, 2024), however overcompensating may exacerbate other health problems in complex conditions including diabetes. Comparative to sutures, bandages, gauzes, and other common medical practices used today, hydrogels as noted have successfully closed wounds without secondary injury and minimal infection risk. The long term effectiveness of hydrogels and their suitability in larger injuries including chronic wounds is important.

References

Samarawickrama, P. N., Zhang, G., Zhu, E., Dong, X., Nisar, A., Zhu, H., Ma, Y., Zhou, Z., Yang, H., Gui, L., Cao, M., Li, W., Chang, Y., Zi, M., Cui, H., Duan, Z., Zhang, X., Li, W., & He, Y. (2024). Clearance of senescent cells enhances skin wound healing in type 2 diabetic mice. https://doi.org/10.7150/thno.100991
Ren, H., Zhang, Z., Cheng, X., Zou, Z., Chen, X., & He, C. (2023). Injectable, self-healing hydrogel adhesives with firm tissue adhesion and on-demand biodegradation for sutureless wound closure. https://doi.org/10.1126/sciadv.adh4327

Ehsanifard, M., Farahpour, M. R., & Tabatabaei, Z. G. (2025). The synergistic effects of linalool and chitosan-carbon nanotubes enhance the healing of infectious wounds. https://doi.org/10.1038/s41598-025-06520-w

Hanin Amara, Fahad Alam, Said El Turk, Haider Butt, 3D-printed and In-situ prepared hydrogel anti-bacterial wound patch with silver nanoparticle embedded matrix, https://doi.org/10.1016/j.heliyon.2025.e42186.

Yu, J., Huang, X., Wu, F., Feng, S., Cheng, R., Xu, J., Cui, T., & Li, J. (2024). 3D-Printed Hydrogel Scaffolds Loaded with Flavanone@ZIF-8 Nanoparticles for Promoting Bacteria-Infected Wound Healing. https://doi.org/10.3390/gels10120835 

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