Scarless Skin Regeneration Research Articles

3D-printed biomimetic scaffold with liposome-encapsulated SB431542 promotes scarless wound healing

Abnormal wound scarring often leads to functional impairments and cosmetic deformities, primarily driven by the prolonged activation of the TGF-β/Smad signaling pathway. Addressing this challenge, we developed a biomimetic scaffold aimed at facilitating rapid and scarless wound healing. This highly integrated 3D-printed dermal scaffold comprised modified recombinant human type III collagen (rhCOLIII-MA), gelatin methacrylate (GelMA), and liposomes encapsulating SB431542 to target TGF-β1 (Lip@SB). The rhCOLIII-MA/GelMA (CG) scaffold retained inherent biomaterial characteristics, exhibited tailored physicochemical properties, and demonstrated favorable biocompatibility. Moreover, the Lip@SB-loaded CG scaffold (CGL) effectively promoted in vitro wound healing, while enabling controlled release of SB431542 to inhibit pathological collagen deposition. In a full-thickness skin defect rat model, the CGL dermal scaffold combined with split-thickness skin graft (STSG) minimized scar contraction, stimulated functional neovascularization, and enhanced graft aesthetics comparable to normal skin. Remarkably, the performance of the CGL scaffold surpassed that of commercially available anti-scarring alternatives. This innovative strategy presents a straightforward approach toward scarless skin regeneration and holds promise in alleviating the prolonged, painful postoperative rehabilitation.

Mechanical biomimetic silk nano fiber-magnesium ion complex/hydroxyethylcellulose/glycerol hydrogel dressing with angiogenic capacity for accelerating scarless diabetic wound healing

Quick scarless healing remains a key issue for diabetic wounds. Here, a stretchable elastomeric hydrogel dressing composed of hydroxyethylcellulose (HEC), silk nano fiber-magnesium ion complex (Mg2+-SNF) and glycerol (Gly) was developed to optimize mechanical niche, anti-inflammatory and angiogenic behavior simultaneously. The composite hydrogel dressing exhibited skin-like elasticity (175.1 ± 23.9 %) and modulus (156.7 ± 2.5 KPa) while Mg2+-SNF complex endowed the dressing with angiogenesis, both favoring quick scarless skin regeneration. In vitro cell studies revealed that the hydrogel dressing stimulated fibroblast proliferation, endothelial cell migration and vessel-like tube formation, and also induced anti-inflammatory behavior of macrophages. In vivo results revealed accelerated healing of diabetic wounds. The improved granulation ingrowth and collagen deposition suggested high quality repair. Both thinner epidermal layer and low collagen I/III ratio of the regenerated skin confirmed scarless tissue formation. This bioactive hydrogel dressing has promising potential to address the multifaceted challenges of diabetic wound management.

A differential-targeting core-shell microneedle patch with coordinated and prolonged release of mangiferin and MSC-derived exosomes for scarless skin regeneration.

Microneedles for skin regeneration are conventionally restricted by uncontrollable multi-drug release, limited types of drugs, and poor wound adhesion. Here, a novel core-shell microneedle patch is developed for scarless skin repair, where the shell is composed of hydrophilic gelatin methacryloyl (GelMA) loaded with mangiferin, an anti-inflammatory small molecule, and the core is composed of hydrophobic poly (lactide-co-propylene glycol-co-lactide) dimethacrylates (PGLADMA) loaded with bioactive macromolecule and human mesenchymal stromal cell (hMSC)-derived exosomes. This material choice provides several benefits: the GelMA shell provides a swelling interface for tissue interlocking and rapid release of mangiferin at an early wound healing stage for anti-inflammation, whereas the PGLADMA core offers long-term encapsulation and release of exosomes (30% release in 3 weeks), promoting sustained angiogenesis and anti-inflammation. Our results demonstrate that the core-shell microneedle possesses anti-inflammatory properties and can induce angiogenesis both in vitro in terms of macrophage polarization and tube formation of human umbilical vein endothelial cells (HUVECs), and in vivo in terms of anti-inflammation, re-epithelization, and vessel formation. Importantly, we also observe reduced scar formation in vivo. Altogether, the degradation dynamics of our hydrophilic/hydrophobic materials enable the design of a core-shell microneedle for differential and prolonged release, promoting scarless skin regeneration, with potential for other therapies of long-term exosome release.

An Injectable Composite Hydrogel of Verteporfin-Bonded Carboxymethyl Chitosan and Oxidized Sodium Alginate Facilitates Scarless Full-Thickness Skin Regeneration.

Full-thickness skin defect has always been a major challenge in clinics due to fibrous hyperplasia in the repair process. Hydrogel composite dressings loaded with anti-fibrotic drugs have been considered as a promising strategy for scarless skin regeneration. In this work, a hydrogel composite (VP-CMCS-OSA) of carboxymethyl chitosan (CMCS) and oxidized sodium alginate (OSA), with loading anti-fibrotic drug verteporfin (VP), is developed based on two-step chemical reactions. Verteporfin is bonded with carboxymethyl chitosan through EDC/NHS treatment to form VP-CMCS, and then VP-CMCS is crosslinked with oxidized sodium alginate by Schiff base reaction to form VP-CMCS-OSA hydrogel. The characterization by SEM, FTIR, and UV-Vis shows the microstructure and chemical bonding of VP-CMCS-OSA. VP-CMCS-OSA hydrogel demonstrates the properties of high tissue adhesion, strong self-healing, and tensile ability. In the full-thickness skin defect model, the VP-CMCS-OSA composite hydrogels hasten wound healing due to the synergistic effects of hydrogels and verteporfin administration. The histological examination reveals the regular collagen arrangement and more skin appendages after VP-CMCS-OSA composite hydrogel treatment, indicating the full-thickness skin regeneration without potential scar formation. The outcomes suggest that the verteporfin-loaded composite hydrogel could be a potential method for scarless skin regeneration.

Efficient scarless skin regeneration enabled by loading micronized amnion in a bioinspired adhesive wound dressing

AbstractComplete skin reconstruction is a hierarchical, physiological assembly process involving healing of the epidermis, dermis, vasculature, nerves, and cutaneous appendages. To date, few works have reported complete skin regeneration, particularly lacking vascular structures and hair follicles after full skin defects. In this study, a hydrogel derived from the skin secretion of Andrias davidianus (SSAD) that features adhesiveness was used as a bioactive scaffold to load micronized amnion (MA). The SSAD hydrogel was found to promote the migration and proliferation of amnion stem cells and human keratinocytes, as well as inhibit their apoptosis in vitro. In a rat full‐skin defect model, the regeneration of skin appendages was observed at the wound area, achieving scarless healing. Transcriptome analyses further validated that SSAD could positively regulate cell migration, proliferation, and differentiation. These functions might be attributed to the abundant growth factors present in the SSAD. Synergized by the delivery of MA, SSAD loaded with the MA could achieve a significantly better skin regeneration effect than SSAD or MA used alone, providing a simple yet highly effective means to obtain complete, scarless skin regeneration, suggesting favorable potential for clinical translation.

Skin Regenerative Potential of Cupuaçu Seed Extract (Theobroma grandiflorum), a Native Fruit from the Amazon: Development of a Topical Formulation Based on Chitosan-Coated Nanocapsules.

Scarless skin regeneration is a challenge in regenerative medicine. Herein, we explore the regenerative potential of a Cupuaçu seed extract (Theobroma grandiflorum) to develop an innovative skin regeneration formulation based on chitosan-coated nanocapsules. Cupuaçu seed extract significantly stimulated cell proliferation and migration. A reparative gene expression profile could be verified following extract treatment, which included high levels of MKI67, a cellular proliferation marker, and extracellular matrix genes, such as ELN and HAS2, which code for elastin and hyaluronic acid synthase 2. Formulations with Cupuaçu seed extract successfully entrapped into nanocapsules (EE% > 94%) were developed. Uncoated or coated nanocapsules with low-molecular-weight chitosan presented unimodal size distribution with hydrodynamic diameters of 278.3 ± 5.0 nm (PDI = 0.18 ± 0.02) and 337.2 ± 2.1 nm (PDI = 0.27 ± 0.01), respectively. Both nanosystems were physically stable for at least 120 days and showed to be non-irritating to reconstructed human epidermis. Chitosan coating promoted active penetration into undamaged skin areas, which were still covered by the stratum corneum. In conclusion, the present study demonstrated for the first time the biotechnological potential of the frequently discarded Cupuaçu seed as a valuable pharmaceutical ingredient to be used in regenerative skin products.

Discovery of Channa StriataExtracts as Regenerative Medicine in Promoting Wound Healing and Scarless Skin Regeneration

Channa striata (also known as Channa striatus) is an air-breathing freshwater snakehead fish that is well known in the Asian region for its medicinal properties, particularly in wound healing. It is recognised as a traditional medicine (TM), which can be served as alternative treatment method. With the advancement of technology, researchers have made a lot of progress in characterising the biomolecules of this fish. Various types of bioactive molecules have been identified in the fish, and their therapeutic effects are being studied. The C. striata have exhibited antibacterial, antinociceptive and effective wound recovery property through various pharmacology assays. It has been regarded as a source of traditional medicine that could complement modern medicine in promoting human health. The applications of C. striata extracts by practitioners in treating different illnesses are discussed. Besides, the approaches towards scarless wound in future applications involving the snakehead fish are also highlighted. Challenges and solutions to develop an aquatic-derived drug were also covered. The Channa striata extract as a natural product has shown great prospects for wound healing enhancement. Many biomolecules associated with antibacterial and antinociceptive properties, which are crucial for healthy wound recovery were identified in the species. Significant advances and researches in the region have successfully led to a better understanding of the species, which provide a promising future for drug development.

Bioactive silk fibroin scaffold with nanoarchitecture for wound healing

Scarless skin regeneration for full-thickness wounds remains a challenge in skin tissue engineering. The surprising scar-free repair function of fetal skin has inspired that the ideal wound dressing can be designed by recapitulating the biophysical and biochemical properties. However, there is no more powerful effective scaffold put into practice due to their mismatched structures and inappropriate components. Here, a novel bioactive scaffold was detailly designed by mimicking extracellular matrix from its chemical components and biophysical nanostructures. Through introduction of hyaluronic acid (HA) and natural silk fibroin nanofibers (SNFs), the silk fibroin (SF)-based scaffolds with higher porosity (~92.5 %), water-uptake ratio (~96 %) and swelling ratio (~90 %) were facilely prepared by lyophilization. In vitro, human umbilical vein endothelial cells (HUVECs) were seeded in the scaffold with nanostructures. The results showed better cytocompatibility of the scaffolds to support cell spread, proliferation and differentiation. In vivo, effect of the scaffolds on full-thickness skin defects of the nude mouse demonstrated that the SNFs incorporated scaffolds could not only accelerated wound healing (up to 98.2 ± 0.5 % within 4 weeks) but also can regulate collagen arrangement by nanofibers as a template to inhibit the scar forming. This study provides a useful strategy for exploring bioactive SF-based scaffolds by natural SNFs decoration for novel wound dressing and artificial skin.

Polyphenol and Cu2+ surface-modified chitin sponge synergizes with antibacterial, antioxidant and pro-vascularization activities for effective scarless regeneration of burned skin

Bacterial overgrowth and high oxidative stress often lead to burn wound infection, hyper-inflammation, and slowed wound healing, eventually causing scar formation. Wound dressings synergized with antibacterial, antioxidant, and pro-vascularization activities can effectively promote wound healing and inhibit scars formation. Herein, chitin sponge consisted of chitin fibers was modified by the coating of proanthocyanidins (PAs) – Cu2+ for effective scarless skin regeneration in a burn injury. The physicochemical characteristics indicated that PAs and Cu2+ successfully modified chitin sponges by the coordination between PAs and Cu2+. For one thing, PAs improved the antioxidant performance of sponges, and for another, with the help of PAs, Cu2+ effectively catalyzed S-nitrosothiols (RSNOs) to continuously generate nitric oxide (NO) in vitro/vivo for improving the inhibition of microorganisms and pro-vascularization activities. Also, Ch/PAs-Cu promoted proliferation of human umbilical vein endothelial cells (HUVECs) and rat fibroblasts (NIH-3T3), and the expression of angiogenic-related cytokines VEGF, eNOS, FGF, and MMP9. In animal experiments, Ch/PAs-Cu inhibited the accumulation of macrophages and neutrophils to regulate wound inflammation while up-regulating the expression of CD31 and α-SMA cytokines to promote angiogenesis. Ultimately, it promoted wound healing and inhibited scar formation. Therefore, Ch/PAs-Cu may be a promising dressing for the scarless repair of burned skin.

Silk gel recruits specific cell populations for scarless skin regeneration

Scarless skin regeneration is not achieved although various biomaterials have been investigated on trial-and-error manner. There is no predictable way to link a specific biomaterial with in vivo cell populations which dominate the skin repair. In this study, single-cell RNA sequencing was conducted to investigate the cellular mechanism of two prevailing biomaterials used in skin regeneration, silk fibroin gel and alginate gel. We found that these two gels induced different cell population structures in vivo. Compared with the alginate-derived hydrogel, silk fibroin-derived hydrogel induced more pro-regenerative macrophages and recruited more hair follicle stem cells, which contributed to almost scarless skin regeneration. Besides, an off-the-shelf silk gel scaffold was fabricated and exhibited more efficacy than autologous skin grafts in porcine models. These findings exhibited the promises of the silk gel for skin regeneration and illustrated a predictable strategy for biomaterial selection based on cell populations recruitment.

Programmable immune activating electrospun fibers for skin regeneration

Immune cells play a crucial regulatory role in inflammatory phase and proliferative phase during skin healing. How to programmatically activate sequential immune responses is the key for scarless skin regeneration. In this study, an “Inner-Outer” IL-10-loaded electrospun fiber with cascade release behavior was constructed. During the inflammatory phase, the electrospun fiber released a lower concentration of IL-10 within the wound, inhibiting excessive recruitment of inflammatory cells and polarizing macrophages into anti-inflammatory phenotype “M2c” to suppress excessive inflammation response. During the proliferative phase, a higher concentration of IL-10 released by the fiber and the anti-fibrotic cytokines secreted by polarized “M2c” directly acted on dermal fibroblasts to simultaneously inhibit extracellular matrix overdeposition and promote fibroblast migration. The “Inner-Outer” IL-10-loaded electrospun fiber programmatically activated the sequential immune responses during wound healing and led to scarless skin regeneration, which is a promising immunomodulatory biomaterial with great potential for promoting complete tissue regeneration.

Asiaticoside-laden silk nanofiber hydrogels to regulate inflammation and angiogenesis for scarless skin regeneration.

Scarless skin regeneration remains a challenge due to the complicated microenvironment involved in wound healing. Here, the hydrophobic drug, asiaticoside (AC), was loaded inside silk nanofiber hydrogels to achieve bioactive and injectable matrices for skin regeneration. AC was dispersed in aqueous silk nanofiber hydrogels with retention of biological functions that regulated inflammatory reactions and vascularization in vitro. After implantation in full-thickness wound defects, these AC-laden hydrogel matrices achieved scarless wound repair. Inflammatory reactions and angiogenesis were regulated during inflammation and remodeling, which was responsible for wound regeneration similar to normal skin. Both in vitro and in vivo studies demonstrated promising applications of these AC-laden silk hydrogels towards scarless tissue regeneration.

Injectable Hydrogels: Microskin‐Inspired Injectable MSC‐Laden Hydrogels for Scarless Wound Healing with Hair Follicles (Adv. Healthcare Mater. 10/2020)

In article number 2000041 by Qiang Lu, Xiaozhong Zhou, Guozhong Lu, and co-workers, microgels composed of aligned silk nanofibers are used to load mesenchymal stem cells (MSCs) to actively modulate the paracrine. The MSCs-laden microgels are blended with injectable silk nanofiber hydrogels to accelerate the wound healing. The synergistic action of MSCs-laden hydrogel systems stimulates angiogenesis and M1-M2 phenotype switching of macrophages, achieving scarless skin regeneration with hair follicles.

Microskin-Inspired Injectable MSC-Laden Hydrogels for Scarless Wound Healing with Hair Follicles.

Scarless skin regeneration with functional tissue remains a challenge for full-thickness wounds. Here, mesenchymal stem cell (MSC)-laden hydrogels are developed for scarless wound healing with hair follicles. Microgels composed of aligned silk nanofibers are used to load MSCs to modulate the paracrine. MSC-laden microgels are dispersed into injectable silk nanofiber hydrogels, forming composites biomaterials containing the cells. The injectable hydrogels protect and stabilize the MSCs in the wounds. The synergistic action of silk-based composite hydrogels and MSCs stimulated angiogenesis and M1-M2 phenotype switching of macrophages, provides a suitable niche for functional recovery of wounds. Compared to skin defects treated with MSC-free hydrogels, the defects treated with the MSC-laden composite hydrogels heal faster and form scarless tissues with hair follicles. Wound healing can be further improved by adjusting the ratio of silk nanofibers and particles and the loaded MSCs, suggesting tunability of the system. To the best of current knowledge, this is the first time scarless skin regeneration with hair follicles based on silk material systems is reported. The improved wound healing capacity of the systems suggests future in vivo studies to compare to other biomaterial systems related to clinical goals in skin regeneration in the absence of scarring.

Bionic Poly(γ-Glutamic Acid) Electrospun Fibrous Scaffolds for Preventing Hypertrophic Scars.

Hypertrophic scarring (HS) remains a great challenge in wound dressing. Although various bionic extracellular matrix (ECM) biomaterials have been designed towards HS treatment, not all biomaterials can synergize biological functions and application functions in wound repair. Bionic scar-inhibiting scaffolds, loaded with biomolecules or drugs, become promising strategies for scarless skin regeneration. In this work, inspired by the physicochemical environment of ECM, a versatile fabrication of poly(γ-glutamic acid) based on electrospun photocrosslinkable hydrogel fibrous scaffolds incorporated with ginsenoside Rg3 (GS-Rg3) is developed for tissue repair and wound therapy. Decorated with adhesive peptide, bionic fibrous scaffolds can accelerate fibroblasts to sprout and grow, forming organized space-filling basement that gradually fills a depression before wound close up in the early stage. Additionally, by sustained release of GS-Rg3 in late stage, fibrous scaffolds promote scarless wound healing in vivo as evidenced by the promotion of cell communication and skin regeneration, as well as the subsequent decrease of angiogenesis and collagen accumulation. These ECM-inspired fibrous scaffolds, therefore, offer new perspectives on accelerated wound healing and tissue regeneration.

Coacervate-mediated exogenous growth factor delivery for scarless skin regeneration

Although there are numerous medical applications to recover damaged skin tissue, scarless wound healing is being extensively investigated to provide a better therapeutic outcome. The exogenous delivery of therapeutic growth factors (GFs) is one of the engineering strategies for skin regeneration. This study presents an exogenous GF delivery platform developed using coacervates (Coa), a tertiary complex of poly(ethylene argininyl aspartate diglyceride) (PEAD) polycation, heparin, and cargo GFs (i.e., transforming growth factor beta 3 (TGF-β3) and interleukin 10 (IL-10)). Coa encompasses the advantage of high biocompatibility, facile preparation, protection of cargo GFs, and sustained GF release. We therefore speculated that coacervate-mediated dual delivery of TGF-β3/IL-10 would exhibit synergistic effects for the reduction of scar formation during physiological wound healing. Our results indicate that the exogenous administration of dual GF via Coa enhances the proliferation and migration of skin-related cells. Gene expression profiles using RT-PCR revealed up-regulation of ECM formation at early stage of wound healing and down-regulation of scar-related genes at later stages. Furthermore, direct injection of the dual GF Coa into the edges of damaged skin in a rat skin wound defect model demonstrated accelerated wound closure and skin regeneration after 3 weeks. Histological evaluation and immunohistochemical staining also revealed enhanced formation of the epidermal layer along with facilitated angiogenesis following dual GF Coa delivery. Based on these results, we conclude that polycation-mediated Coa fabrication and exogenous dual GF delivery via the Coa platform effectively augments both the quantity and quality of regenerated skin tissues without scar formation. Statement of SignificanceThis study was conducted to develop a simple administration platform for scarless skin regeneration using polycation-based coacervates with dual GFs. Both in vitro and in vivo studies were performed to confirm the therapeutic efficacy of this platform toward scarless wound healing. Our results demonstrate that the platform developed by us enhances the proliferation and migration of skin-related cells. Sequential modulation in various gene expression profiles suggests a balanced collagen-remodeling process by dual GFs. Furthermore, in vivo histological evaluation demonstrates that our technique enhances clear epidermis formation with less scab and thicker woven structure of collagen bundle, similar to that of a normal tissue. We propose that simple administration of dual GFs with Coa has the potential to be applied as a clinical approach for fundamental scarless skin regeneration.

A ZnO-curcumin nanocomposite embedded hybrid collagen scaffold for effective scarless skin regeneration in acute burn injury.

Scar formation in severe burn injury is a major health concern. Herein, we developed a hybrid collagen scaffold with an incorporated ZnO-curcumin nanocomposite, which facilitates scarless wound healing. Biocompatibility and hemocompatibility studies unveiled that the hybrid scaffold is apt for in vivo wound healing studies. Histological and immunohistochemical analyses demonstrate that the hybrid scaffold accelerated scarless burn wound healing in albino rats owing to the ZnO-curcumin nanocomposite induced up-regulation of angiogenesis and TGF-β3 expression. The semi-quantitatively measured scar elevation index of the hybrid scaffold-treated animals is on a par with that of the unwounded or normal skin. The studies suggest that the prepared hybrid biomaterial could be a potential candidate for scarless healing in severe burn injuries.

N-acetyl cysteine-loaded graphene oxide-collagen hybrid membrane for scarless wound healing.

Wound dressings composed of natural polymers, such as type I collagen, possess good biocompatibility, water holding capacity, air permeability, and degradability, and can be used in wound repair. However, due to the persistent oxidative stress in the wound area, the migration and proliferation of fibroblasts might be suppressed, leading to poor healing. Thus, collagen-containing scaffolds are not suitable for accelerated wound healing. Antioxidant N-acetyl cysteine (NAC) is known to reduce the reactive oxygen species (ROS) and has been widely used in the clinic. Theoretically, the carboxyl group of NAC allows loading of graphene oxide (GO) for sustained release and may also enhance the mechanical properties of the collagen scaffold, making it a better wound-dressing material. Herein, we demonstrated an innovative approach for a potential skin-regenerating hybrid membrane using GO incorporated with collagen I and NAC (N-Col-GO) capable of continuously releasing antioxidant NAC.Methods: The mechanical stability, water holding capacity, and biocompatibility of the N-Col-GO hybrid membrane were measured in vitro. A 20 mm rat full-skin defect model was created to evaluate the repair efficiency of the N-Col-GO hybrid membrane. The vascularization and scar-related genes in the wound area were also examined.Results: Compared to the Col only scaffold, N-Col-GO hybrid membrane exhibited a better mechanical property, stronger water retention capacity, and slower NAC release ability, which likely promote fibroblast migration and proliferation. Treatment with the N-Col-GO hybrid membrane in the rat wound model showed complete healing 14 days after application which was 22% faster than the control group. HE and Masson staining confirmed faster collagen deposition and better epithelization, while CD31 staining revealed a noticeable increase of vascularization. Furthermore, Rt-PCR demonstrated decreased mRNA expression of profibrotic and overexpression of anti-fibrotic factors indicative of the anti-scar effect.Conclusion: These findings suggest that N-Col-GO drug release hybrid membrane serves as a better platform for scarless skin regeneration.

Engineering Pro-Regenerative Hydrogels for Scarless Wound Healing.

Skin and skin appendages protect the body from harmful environment and prevent internal organs from dehydration. Superficial epidermal wounds usually heal without scarring, however, deep dermal wound healing commonly ends up with nonfunctioning scar formation with substantial loss of skin appendage. Wound healing is one of the most complex dynamic biological processes, during which a cascade of biomolecules combine with stem cell influx and matrix synthesis and synergistically contribute to wound healing at all levels. Although many approaches have been investigated to restore complete skin, the clinically effective therapy is still unavailable and the regeneration of perfect skin still remains a significant challenge. The complete mechanism behind scarless skin regeneration still requires further investigation. Fortunately, recent advancement in regenerative medicine empowers us more than ever to restore tissue in a regenerative manner. Many studies have elucidated and reviewed the contribution of stem cells and growth factors to scarless wound healing. This article focuses on recent advances in scarless wound healing, especially strategies to engineer pro-regenerative scaffolds to restore damaged skin in a regenerative manner.

Natural healing-inspired collagen-targeting surgical protein glue for accelerated scarless skin regeneration

Skin scarring after deep dermal injuries is a major clinical problem due to the current therapies limited to established scars with poor understanding of healing mechanisms. From investigation of aberrations within the extracellular matrix involved in pathophysiologic scarring, it was revealed that one of the main factors responsible for impaired healing is abnormal collagen reorganization. Here, inspired by the fundamental roles of decorin, a collagen-targeting proteoglycan, in collagen remodeling, we created a scar-preventive collagen-targeting glue consisting of a newly designed collagen-binding mussel adhesive protein and a specific glycosaminoglycan. The collagen-targeting glue specifically bound to type I collagen in a dose-dependent manner and regulated the rate and the degree of fibrillogenesis. In a rat skin excisional model, the collagen-targeting glue successfully accelerated initial wound regeneration as defined by effective reepithelialization, neovascularization, and rapid collagen synthesis. Moreover, the improved dermal collagen architecture was demonstrated by uniform size of collagen fibrils, their regular packing, and a restoration of healthy tissue component. Collectively, our natural healing-inspired collagen-targeting glue may be a promising therapeutic option for improving the healing rate with high-quality and effective scar inhibition.