Injectable NANO-bioactive scaffold for controlled release of growth factors and tissue regeneration
Patent Information
- Application Number
- PCT/IB2025/051708
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- Filing Date
- 2025-02-18
- Publication Date
- 2026-08-27
Smart Images
Figure IB2025051708_27082026_PF_FP_ABST
Abstract
Description
INJECTABLE NANO-BIOACTIVE SCAFFOLD FOR CONTROLLED RELEASE OF GROWTH FACTORS AND TISSUE REGENERATIONTECHNICAL FIELD
[0001] The present invention pertains to the fields of regenerative medicine, tissue engineering, and biomaterials. It discloses an injectable nano-bioactive scaffold designed to replace or augment conventional dermal fillers and injectable gels. The scaffold provides controlled release of bioactive molecules, such as growth factors, to promote long-term tissue regeneration. Applications include dentistry (gingival regeneration), plastic surgery (facial rejuvenation), and reconstructive surgery (soft-tissue defect repair), offering enhanced biocompatibility and sustained therapeutic effects.BACKGROUND ART
[0002] Injectable gels and dermal fillers, such as those based on hyaluronic acid (HA), have been widely used in aesthetic and reconstructive medicine for temporary volume restoration. However, these materials often lack bioactivity, providing only passive structural support without stimulating natural tissue regeneration. Their effects are typically short-lived, lasting only a few months, necessitating repeated injections. Furthermore, some fillers may induce inflammatory responses or encapsulation by surrounding tissues, which can compromise clinical outcomes and patient satisfaction.
[0003] Recent advancements in tissue engineering have highlighted the potential of bioactive scaffolds that not only provide mechanical support but also deliver therapeutic agents to actively promote tissue healing and regeneration. Growth factors, such as Fibroblast Growth Factor (FGF), Vascular Endothelial Growth Factor (VEGF), and Transforming Growth Factorbeta (TGF-P), play critical roles in cell proliferation, angiogenesis, and extracellular matrix (ECM) remodeling. However, their direct application is limited by rapid degradation and poor localization in vivo.
[0004] To address these challenges, researchers have explored various polymer-based systems, including HA, chitosan, and alginate, for their biocompatibility and ability to form hydrogels. These materials can be chemically modified to achieve tunable mechanical properties, injectability, and in situ gelation. Additionally, nano -structured reinforcements, such as mesoporous silica nanoparticles (MSNs) and electrospun nanofibers, have been incorporated to enhance mechanical strength, modulate biodegradation rates, and improve cell adhesion.
[0005] Despite these advancements, existing systems often fail to integrate multiple functionalities required for clinical efficacy. For instance, many scaffolds lack the ability to control the release of multiple growth factors over extended periods, which is critical for sustained tissue regeneration. Moreover, achieving a balance between injectability, rapid in situ gelation, and mechanical stability remains a significant challenge.
[0006] Another limitation of current technologies is the inability to tailor release profiles to specific physiological conditions. For example, growth factors may need to be released in response to local pH changes, enzymatic activity, or inflammation levels to maximize therapeutic efficacy. While some systems have incorporated stimuli-responsive mechanisms, they often lack the precision and versatility needed for diverse clinical applications.
[0007] Furthermore, conventional fillers and scaffolds may not adequately address the inflammatory and microbial risks associated with implantation. Although some materials, such as chitosan, exhibit intrinsic antibacterial properties, the integration of additional antiinflammatory or antimicrobial agents, such as metallic nanoparticles, has been underexplored in injectable systems.
[0008] In light of these limitations, there is a pressing need for an integrated, multi-functional injectable scaffold that combines injectability, rapid in situ gelation, controlled release of bioactive molecules, and enhanced tissue regeneration. Such a system would not only extend the therapeutic effect but also reduce the need for repeated injections and minimize inflammatory risks.
[0009] The present invention addresses these unmet needs by providing a nano-bioactive scaffold that integrates a biocompatible hydrogel base, nano -structured reinforcements, and encapsulated growth factors with controlled release mechanisms. This innovative approach offers a versatile solution for applications in dentistry, plastic surgery, and reconstructive surgery, paving the way for improved clinical outcomes and patient care.SUMMARY OF THE DISCLOSURE
[0010] This summary is intended to provide an overview of the subject matter of the present disclosure, and is not intended to identify essential elements or key elements of the subject matter, nor is it intended to be used to determine the scope of the claimed implementations. The proper scope of the present disclosure may be ascertained from the claims set forth below in view of the detailed description below and the drawings.
[0011] The present invention focuses on the development of an injectable nano-bioactive scaffold, specifically designed for controlled release of growth factors and enhanced tissue regeneration. This scaffold is composed of a biocompatible hydrogel base that includes methacrylated hyaluronic acid (HA-MA) within a concentration range of 1% to 3% (w / v), ensuring optimal support for tissue regeneration.
[0012] The hydrogel base is further enriched with carbodiimide-mediated hyaluronic acid and partially deacetylated chitosan, containing positively charged amino groups to enhance cellular interactions. The concentration of chitosan ranges from 0.5% to 2% (w / w). Alginate is also incorporated within a 2% to 4% (w / w) range, providing additional structural integrity to the hydrogel.
[0013] Self-assembling peptides, specifically RADA 16 peptide, are included in concentrations between 0.2% and 0.7% (w / v) to promote cellular attachment and proliferation. Chemical crosslinkers such as l-Ethyl-3 -(3 -dimethylaminopropyl) carbodiimide (EDC), N-Hydroxy succinimide (NHS), and genipin are utilized to ensure the stability and durability of the scaffold.
[0014] To further enhance the scaffold's properties, nano -structured reinforcements are integrated. These include mesoporous silica nanoparticles, with pore sizes ranging from 2 to 50 nanometers and concentrations between 0.1 (mg / ml) and 0.3 (mg / ml), providing a high surface area for growth factor attachment. Electrospun collagen nanofibers (0.4% to 0.6% w / w), gelatin nanofibers, Poly(lactic-co-glycolic acid) (PLGA) nanofibers, silver nanoparticles, copper nanoparticles, and zinc oxide nanoparticles are also incorporated for their synergistic effects on tissue regeneration.
[0015] The scaffold is loaded with crucial growth factors, such as fibroblast growth factor (FGF), liposomal vascular endothelial growth factor (VEGF) within a range of 0.5 to 1.5 (pg / mL), and transforming growth factor-beta (TGF-P). These growth factors are essential forpromoting angiogenesis, cell proliferation, and differentiation, ensuring effective and sustained tissue regeneration.
[0016] A specific embodiment of the injectable nano-bioactive scaffold includes optimized concentrations: 2% (w / v) HA-MA, 1% (w / w) partially deacetylated chitosan, 3% (w / w) alginate, 0.5% (w / v) RADA 16 peptide, mesoporous silica nanoparticles with 25 nanometer pore sizes at 0.2 (mg / ml), 0.5% (w / w) electrospun collagen nanofibers, and 1 (pg / mL) liposomal VEGF. These optimized concentrations have demonstrated superior performance in preclinical studies.
[0017] The method for preparing this scaffold involves mixing the hydrogel components, incorporating the nano -structured reinforcements, and finally, adding the growth factors. This method ensures a uniform distribution of all components, providing a consistent and effective delivery system for the controlled release of growth factors.
[0018] Additionally, an injectable hydrogel specifically designed for gingival regeneration is disclosed. This hydrogel comprises 2% (w / v) HA-MA, 1% (w / w) partially deacetylated chitosan, mesoporous silica nanoparticles within a range of 0.1 to 0.3 (mg / ml) and pore sizes between 2 and 50 nanometers, and 0.5% (w / v) RADA16 peptide. This formulation has shown promise in promoting gingival tissue regeneration and reducing inflammation.
[0019] In conclusion, the injectable nano-bioactive scaffold described in this invention represents a significant advancement in tissue engineering and regenerative medicine. By providing immediate volumization and sustained release of growth factors, it offers superior clinical outcomes, reduces the need for repeated interventions, and minimizes inflammatory complications. This innovative approach holds great potential for various applications in soft tissue repair and regeneration.BRIEF DESCRIPTION OF THE DRAWINGS
[0020] The drawing figures depict one or more implementations in accord with the present teachings, by way of example only, not by way of limitation. In the figures, like reference numerals refer to the same or similar elements.
[0021] FIG. 1 illustrates a method for preparing an injectable nano-bioactive scaffold for controlled release of growth factors and tissue regeneration, consistent with one or more exemplary embodiments of the present disclosure.DESCRIPTION OF EMBODIMENTS
[0022] In the following detailed description, numerous specific details are set forth by way of examples in order to provide a thorough understanding of the relevant teachings. However, it should be apparent that the present teachings may be practiced without such details. In other instances, well known methods, procedures, components, and / or circuitry have been described at a relatively high-level, without detail, in order to avoid unnecessarily obscuring aspects of the present teachings.
[0023] The following detailed description is presented to enable a person skilled in the art to make and use the methods and devices disclosed in exemplary embodiments of the present disclosure. For purposes of explanation, specific nomenclature is set forth to provide a thorough understanding of the present disclosure. However, it will be apparent to one skilled in the art that these specific details are not required to practice the disclosed exemplary embodiments. Descriptions of specific exemplary embodiments are provided only as representative examples. Various modifications to the exemplary implementations will be readily apparent to one skilled in the art, and the general principles defined herein may be applied to other implementations and applications without departing from the scope of the present disclosure. The present disclosure is not intended to be limited to the implementations shown, but is to be accorded the widest possible scope consistent with the principles and features disclosed herein.
[0024] Disclosed herein is an injectable nano-bioactive scaffold for controlled release of growth factors and tissue regeneration. In an exemplary embodiment, injectable nano-bioactive scaffold may include a biocompatible hydrogel base. In an exemplary embodiment, the biocompatible hydrogel base may include an amount of methacrylated hyaluronic acid (HAMA). In an exemplary embodiment, the amount of methacrylated hyaluronic acid (HA-MA) may be in a range between 1% (w / v) and 3% (w / v). In an exemplary embodiment, the amount of methacrylated hyaluronic acid (HA-MA) may be 2% (w / v). In an exemplary embodiment, the biocompatible hydrogel base may further include an amount of carbodiimide-mediated hyaluronic acid. For purpose of reference, it may be understood that Modified Hyaluronic Acid (HA) plays a crucial role in the nano-bioactive scaffold due to its natural presence in the extracellular matrix, exceptional biocompatibility, and high water retention capacity. These properties make HA an ideal candidate for supporting tissue regeneration. The modification of HA involves methacrylation (HAMA), which allows for photocrosslinking or free radical polymerization, enhancing the mechanical stability and durability of the scaffold. Additionally,carbodiimide-mediated crosslinking enables the formation of amide bonds with functional groups on chitosan or collagen, further strengthening the scaffold's structure. This combination of biocompatibility and chemical modifications ensures that Modified HA provides a supportive and long-lasting environment for effective tissue regeneration.
[0025] In an exemplary embodiment, the biocompatible hydrogel base may further include an amount of partially deacetylated chitosan with positively charged amino groups. In an exemplary embodiment, the amount of partially deacetylated chitosan may be in a range between 0.5% (w / w) and 2% (w / w). Specifically, in an exemplary embodiment, the amount of partially deacetylated chitosan may be 1% (w / w). In an exemplary embodiment, the biocompatible hydrogel base may further include an amount of alginate. In an exemplary embodiment, the amount of alginate may be in a range between 2% (w / w) and 4% (w / w). Specifically, in an exemplary embodiment, the amount of alginate may be 3% (w / w).
[0026] In an exemplary embodiment, it may be understood that chitosan, partially deacetylated and containing positively charged amino groups, is a valuable component in the nano-bioactive scaffold due to its ability to form ionic crosslinks with substances such as sodium tripolyphosphate (TPP) or polyanionic polymers. This crosslinking capability enhances the structural integrity of the scaffold. Additionally, chitosan possesses intrinsic antibacterial properties attributed to its cationic nature, which helps in preventing infections during the tissue regeneration process.
[0027] Furthermore, it may also be understood that alginate, another essential component, forms a hydrogel when exposed to divalent cations like calcium (Ca2+). This property makes it particularly effective for in situ gelation upon injection, especially in environments rich in calcium or when a separate crosslinking agent is administered. Alginate's ability to form hydrogels in the body ensures that the scaffold remains in place, providing a stable matrix for tissue regeneration and repair.
[0028] In an exemplary embodiment, the bio compatible hydrogel base may further include self-assembling peptides. In an exemplary embodiment, the self-assembling peptides may include an amount of RADA 16 peptide. In an exemplary embodiment, the amount of RADA 16 peptide may be in a range between 0.2% (w / v) and 0.7% (w / v). Specifically, in an exemplary embodiment, the amount of RADA16 peptide may be 0.5% (w / v). In an exemplary embodiment, it may be understood that self-Assembling Peptides (SAPs), such as synthetic peptides like RADA 16, are a valuable addition to the nano-bioactive scaffold. These peptideshave the unique ability to spontaneously form nanofibrous networks when exposed to physiological conditions. This self-assembly process enhances cell adhesion, providing a conducive environment for cell growth and proliferation. Furthermore, the formation of these nanofibrous networks improves the mechanical integrity of the scaffold, making it more robust and durable for effective tissue regeneration. The incorporation of SAPs thus significantly contributes to the scaffold's overall functionality and performance in regenerative medicine applications.
[0029] In an exemplary embodiment, the bio compatible hydrogel base may further include chemical crosslinkers. In an exemplary embodiment, the chemical crosslinkers may include an amount of l-Ethyl-3 -(3 -dimethylaminopropyl) carbodiimide (EDC), an amount of billy droxy succinimide (NHS), and an amount of genipin. In an exemplary embodiment, it may be understood that crosslinking and degradation rate are crucial aspects of the nano -bioactive scaffold, ensuring it meets specific mechanical and biological requirements. The scaffold can be crosslinked using chemical agents such as EDC / NHS and genipin, or through physical methods like ionic crosslinking and thermal gelation. By tuning the crosslink density, it is possible to control the mechanical strength and swelling behavior of the scaffold. This adjustment also influences the rate at which the scaffold degrades in vivo, allowing for tailored degradation profiles that match the needs of the tissue regeneration process. Careful control over these factors ensures that the scaffold provides effective support throughout the healing process and gradually degrades as new tissue forms.
[0030] In an exemplary embodiment, the injectable nano-bioactive scaffold may further include nano-structured reinforcements. In an exemplary embodiment, the nano -structured reinforcements may include an amount of mesoporous silica nanoparticles. In an exemplary embodiment, pore sizes of the amount of mesoporous silica nanoparticles may be in a range between 2 nanometers and 50 nanometers. Specifically, in an exemplary embodiment, pore sizes of the amount of mesoporous silica nanoparticles may be 25 nanometers. In an exemplary embodiment, the amount of mesoporous silica nanoparticles may be in a range between 0.1 (mg / ml) and 0.3 (mg / ml). Specifically, in an exemplary embodiment, the amount of mesoporous silica nanoparticles may be 0.2 (mg / ml).
[0031] For purpose of reference, it may be understood that Mesoporous Silica Nanoparticles (MSNs) are a vital component in the nano-bioactive scaffold, characterized by their unique structure and functionality. These nanoparticles feature pore sizes ranging from 2 to 50nanometers, which enable them to load and deliver large biomolecules such as proteins or nucleic acids. This capability is essential for the controlled release of therapeutic agents, ensuring they are delivered precisely where needed for effective tissue regeneration.
[0032] The surface of MSNs can be functionalized with amino or carboxyl groups to enhance their dispersibility within the hydrogel matrix. This surface modification helps the nanoparticles integrate more seamlessly with the scaffold, promoting uniform distribution and stability. The improved dispersibility also ensures that the therapeutic agents loaded within the MSNs are evenly distributed throughout the scaffold, maximizing their efficacy.
[0033] Another significant advantage of MSNs is their controlled degradation. When introduced into the body, these nanoparticles gradually dissolve in bodily fluids, converting into orthosilicic acid. This process ensures that the MSNs are biocompatibly cleared from the body without causing any adverse reactions. The gradual degradation also means that the release of therapeutic agents is sustained over time, providing a continuous supply of bioactive molecules that support long-term tissue regeneration.
[0034] In summary, Mesoporous Silica Nanoparticles enhance the functionality of the nanobioactive scaffold through their ability to load large biomolecules, their improved dispersibility due to surface functionalization, and their controlled, biocompatible degradation. These features make MSNs an indispensable component for advanced tissue engineering applications.
[0035] In an exemplary embodiment, the nano -structured reinforcements may further include an amount of electrospun collagen nanofibers. In an exemplary embodiment, the amount of electrospun collagen nanofibers may be in a range between 0.4 (w / w) and 0.6 (w / w). Specifically, in an exemplary embodiment, the amount of electrospun collagen nanofibers may be 0.5 (w / w). In an exemplary embodiment, the nano -structured reinforcements may further include an amount of gelatin nanofibers. In an exemplary embodiment, the nano-structured reinforcements may further include Poly(lactic-co-glycolic acid) (PLGA) nanofibers.
[0036] For purpose of reference, it may be understood that electrospun nanofibers made from collagen or gelatin play a critical role in the nano -bioactive scaffold by closely mimicking the natural extracellular matrix (ECM). This structural similarity enhances cell attachment and proliferation, providing a supportive environment for tissue regeneration. Collagen and gelatin nanofibers promote cellular interactions, which are essential for effective tissue repair and integration.
[0037] Poly(lactic-co-glycolic acid) (PLGA) fibers, another integral component, are a biodegradable polymer with controllable degradation rates. The degradation rate of PLGA fibers can be precisely tuned by adjusting the lactide-to-glycolide ratio. This flexibility allows for the scaffold to be customized to match the specific needs of the tissue regeneration process. As the PLGA fibers degrade, they provide a sustained release of bioactive molecules, further supporting the tissue regeneration process and ensuring the scaffold gradually disappears as new tissue forms.
[0038] Together, electrospun collagen or gelatin nanofibers and PLGA fibers contribute significantly to the mechanical strength, biocompatibility, and effectiveness of the nanobioactive scaffold, making it a versatile tool in regenerative medicine applications.
[0039] In an exemplary embodiment, the nano -structured reinforcements may further include an amount of silver nanoparticles, an amount of copper nanoparticles, and an amount of zinc oxide nanoparticles. For purpose of reference, it may be understood that metallic or metal oxide nanoparticles, such as silver or copper nanoparticles, play a significant role in the nanobioactive scaffold due to their anti-inflammatory and antibacterial properties. These nanoparticles help in reducing inflammation and preventing bacterial infections during the tissue regeneration process, thereby promoting a healthier healing environment. Additionally, zinc oxide nanoparticles offer potential immunomodulatory and antimicrobial effects. These nanoparticles can modulate the immune response, ensuring that the body's natural defense mechanisms support the tissue regeneration process while also preventing microbial infections. Together, the inclusion of silver, copper, and zinc oxide nanoparticles enhances the overall efficacy and safety of the scaffold, making it a more robust and reliable tool for regenerative medicine.
[0040] In an exemplary embodiment, the nano -structured reinforcements may further include growth factors. In an exemplary embodiment, the growth factors may include an amount of fibroblast growth factor (FGF), an amount of liposomal vascular endothelial growth factor (VEGF), and an amount of transforming growth factor-beta (TGF-P). In an exemplary embodiment, the amount of liposomal vascular endothelial growth factor (VEGF) may be in a range between 0.5 (pg / mL) and 1.5 (pg / mL). Specifically, in an exemplary embodiment, the amount of liposomal vascular endothelial growth factor (VEGF) may be 1 (pg / mL).
[0041] For purpose of reference it may be understood that growth factors play a pivotal role in the nano-bioactive scaffold by promoting various essential biological processes. FibroblastGrowth Factor (FGF) is instrumental in stimulating the proliferation of fibroblasts, which are critical cells for wound healing and tissue repair. It also enhances collagen synthesis, providing the structural framework necessary for regenerating tissues.
[0042] Vascular Endothelial Growth Factor (VEGF) is crucial for inducing angiogenesis, the formation of new blood vessels from pre-existing ones. This process significantly improves the nutrient and oxygen supply to the regenerating tissue, ensuring that the cells receive the essential resources they need for growth and repair. VEGF's role in angiogenesis is vital for the overall success of tissue regeneration.
[0043] Transforming Growth Factor-beta (TGF-P) plays a key role in modulating the remodeling of the extracellular matrix (ECM), which is the complex network of proteins and other molecules that provide structural and biochemical support to surrounding cells. TGF-P helps in maintaining the balance of ECM components, promoting proper tissue architecture. Additionally, TGF-P reduces chronic inflammation, creating a more favorable environment for tissue regeneration and healing.
[0044] Together, FGF, VEGF, and TGF-P significantly enhance the efficacy of the nanobioactive scaffold by stimulating cell proliferation, improving nutrient supply, and modulating the ECM, leading to more effective and sustained tissue regeneration.
[0045] For purpose of reference, it may be understood that encapsulation strategies in the nanobioactive scaffold involve several advanced techniques to ensure controlled release of growth factors. Liposomes or nanoliposomes are utilized to encapsulate growth factors within their aqueous core. The lipid composition, including components such as DSPC and cholesterol, along with surface modifications like PEGylation, allows for controlled degradation in vivo. This ensures a sustained release of growth factors over time, enhancing the scaffold's effectiveness.
[0046] Mesoporous Silica Nanoparticles (MSNs) with gatekeepers present another sophisticated encapsulation method. Growth factors can be physically adsorbed or chemically conjugated to the internal pore surfaces of the MSNs. The pores are then “capped” with biodegradable polymers such as chitosan or enzyme-sensitive peptides, ensuring a delayed and triggered release of the growth factors. This method allows for precise control over the release timing, ensuring that growth factors are delivered when needed most.
[0047] Polyelectrolyte complexes involve electrostatic interactions between negatively charged growth factors or associated polypeptides and positively charged chitosan. Theseinteractions result in the formation of nano- or micro-complexes that slowly dissociate under physiological conditions. This gradual dissociation ensures a sustained and controlled release of the growth factors, supporting continuous tissue regeneration.
[0048] Regarding release profiles, diffusion-controlled release is driven by concentration gradients through the hydrogel matrix. This is particularly relevant for low -molecular- weight agents or those situated near the surface of the scaffold. Degradation-controlled release involves the hydrolytic or enzymatic degradation of the hydrogel network by enzymes such as hyaluronidase or lysozymes, which gradually exposes the encapsulated growth factors. The rates of degradation can be fine-tuned by adjusting the crosslink density and polymer composition of the scaffold.
[0049] Stimuli-responsive release mechanisms involve segments of the scaffold that are responsive to specific stimuli. For instance, pH-responsive segments like chitosan can swell or contract, affecting the diffusion of molecules. Enzyme -responsive peptides degrade specifically at sites of high enzymatic activity, such as inflamed or injured tissue, ensuring targeted release of growth factors where they are needed most.
[0050] These advanced encapsulation strategies and release profiles ensure that growth factors are delivered in a controlled and sustained manner, significantly enhancing the effectiveness of the nano-bioactive scaffold in promoting tissue regeneration and repair.
[0051] Disclosed herein is also a method for preparing an injectable nano-bioactive scaffold for controlled release of growth factors and tissue regeneration. FIG. 1 shows a method 100 for preparing an injectable nano-bioactive scaffold for controlled release of growth factors and tissue regeneration, consistent with one or more exemplary embodiments of the present disclosure. As shown in FIG. 1, in an exemplary embodiment, method 100 may include a first step 101 of preparing a biocompatible hydrogel base, a second step 102 of adding nanostructured reinforcements to the biocompatible hydrogel base, and a third step 103 of adding growth factors to the biocompatible hydrogel base.
[0052] In an exemplary embodiment, in order to implement first step 101, an amount of methacrylated hyaluronic acid (HA-MA), an amount of carbodiimide-mediated hyaluronic acid, an amount of partially deacetylated chitosan with positively charged amino groups, an amount of alginate, an amount of RADA 16 peptide, an amount of l-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), an amount of N-Hydroxy succinimide (NHS), and an amount of genipin may be mixed. In an exemplary embodiment, the amount ofmethacrylated hyaluronic acid (HA-MA) may be between 1% (w / v) and 3% (w / v). In an exemplary embodiment, the amount of partially deacetylated chitosan may be between 0.5% (w / w) and 2% (w / w). In an exemplary embodiment, the amount of alginate may be in a range between 2% (w / w) and 4% (w / w). In an exemplary embodiment, the amount of RADA 16 peptide may be in a range between 0.2% (w / v) and 0.7% (w / v).
[0053] In an exemplary embodiment, in order to implement second step 102, nano-structured reinforcements may be added to the biocompatible hydrogel base. In an exemplary embodiment, the nano -structured reinforcements may include an amount of mesoporous silica nanoparticles. In an exemplary embodiment, pore sizes of the amount of mesoporous silica nanoparticles may be in a range between 2 nanometers and 50 nanometers. Specifically, in an exemplary embodiment, pore sizes of the amount of mesoporous silica nanoparticles may be 25 nanometers. In an exemplary embodiment, the amount of mesoporous silica nanoparticles may be in a range between 0.1 (mg / ml) and 0.3 (mg / ml). Specifically, in an exemplary embodiment, the amount of mesoporous silica nanoparticles may be 0.2 (mg / ml).
[0054] In an exemplary embodiment, the nano -structured reinforcements may further include an amount of electrospun collagen nanofibers. In an exemplary embodiment, the amount of electrospun collagen nanofibers may be in a range between 0.4 (w / w) and 0.6 (w / w). Specifically, in an exemplary embodiment, the amount of electrospun collagen nanofibers may be 0.5 (w / w). In an exemplary embodiment, the nano -structured reinforcements may further include an amount of gelatin nanofibers. In an exemplary embodiment, the nano-structured reinforcements may further include Poly(lactic-co-glycolic acid) (PLGA) nanofibers. In an exemplary embodiment, the nano-structured reinforcements may further include an amount of silver nanoparticles, an amount of copper nanoparticles, and an amount of zinc oxide nanoparticles.
[0055] In an exemplary embodiment, in order to implement third step 103, growth factors may be added to the biocompatible hydrogel base. In an exemplary embodiment, the nanostructured reinforcements may further include growth factors. In an exemplary embodiment, the growth factors may include an amount of fibroblast growth factor (FGF), an amount of liposomal vascular endothelial growth factor (VEGF), and an amount of transforming growth factor-beta (TGF-P). In an exemplary embodiment, the amount of liposomal vascular endothelial growth factor (VEGF) may be in a range between 0.5 (pg / mL) and 1.5 (pg / mL).Specifically, in an exemplary embodiment, the amount of liposomal vascular endothelial growth factor (VEGF) may be 1 (pg / mL).
[0056] As discussed above, the innovative injectable nano-bioactive scaffold offers numerous applications and benefits across various medical fields, significantly advancing the state of regenerative medicine and clinical treatments.
[0057] One of the primary applications of this scaffold lies in the field of dentistry. It is particularly effective for gingival regeneration, where it stimulates soft tissue regrowth around teeth or dental implants. This leads to improved oral health and aesthetics, providing a solution for patients suffering from gum recession or damage due to periodontal disease. Additionally, the controlled release of growth factors within the scaffold promotes fibroblast proliferation and vascularization, aiding in the repair of periodontal defects. This results in more effective healing and regeneration of the periodontal tissues, ensuring long-term oral health benefits.
[0058] In aesthetic medicine, the scaffold is highly beneficial for facial rejuvenation. It provides volume restoration and tissue regeneration, reducing the need for frequent reinjections often required with traditional fillers. This makes it an ideal solution for those seeking long-lasting cosmetic improvements. Moreover, the scaffold enhances the remodeling of the dermal extracellular matrix (ECM), making it effective for scar revision. Patients with acne scars, surgical scars, or other dermal imperfections can benefit from this treatment, as it promotes smoother and healthier skin.
[0059] The scaffold's applications extend to reconstructive surgery, where it plays a crucial role in repairing soft tissue defects. Its ability to heal large or irregular defects through endogenous tissue formation makes it invaluable for patients recovering from trauma or surgery. In particular, the scaffold supports tissue regeneration in areas that have been irradiated or excised due to oncologic surgeries. This is essential for cancer patients, as it aids in the restoration of tissues and reduces complications associated with traditional reconstructive methods.
[0060] Compared to conventional fillers, the injectable nano-bioactive scaffold offers several significant advantages. Its longer-lasting effect is attributed to the sustained release of bioactive molecules, ensuring continuous support for tissue regeneration over an extended period. This sustained release reduces the frequency of injections required, making it more convenient and cost-effective for patients. Additionally, the use of biocompatible polymers and antiinflammatory nano-additives minimizes inflammation, creating a more favorable environmentfor healing and reducing the risk of adverse reactions. Unlike passive volume replacement offered by traditional fillers, the scaffold actively promotes tissue regeneration, leading to more natural and durable results.
[0061] In summary, the injectable nano-bioactive scaffold's clinical applications and benefits span dentistry, aesthetic medicine, and reconstructive surgery, offering enhanced tissue regeneration, reduced inflammation, and longer-lasting effects compared to conventional treatments. This groundbreaking invention holds the potential to revolutionize various medical fields, providing patients with more effective and sustainable solutions for tissue repair and regeneration.Example 1: Injectable Hydrogel for Gingival Regeneration
[0062] In this example, the formulation of the injectable hydrogel for gingival regeneration includes 2% (w / v) methacrylated hyaluronic acid (HA), 1% chitosan, mesoporous silica nanoparticles (MSNs) loaded with fibroblast growth factor (FGF) at a concentration of 0.2 mg / mL, and RADA 16 peptide at 0.5% (w / v). The procedure involves pre-mixing these components under sterile conditions to ensure a contamination-free environment. Postinjection, gentle UV exposure for less than one minute initiates the crosslinking process, stabilizing the hydrogel. The outcome of this formulation and procedure is promising, as in vitro tests demonstrate a sustained release of FGF over 21 days. This prolonged release significantly promotes fibroblast proliferation on scaffold surfaces, which is crucial for effective gingival tissue regeneration.Example 2: Nano-Bioactive Dermal Filler
[0063] For the nano-bioactive dermal filler, the formulation consists of 3% alginate, 0.5% electrospun collagen nanofibers, liposomal vascular endothelial growth factor (VEGF) at 1 pg / mL, and genipin as a mild crosslinker. The procedure involves injecting this formulation subcutaneously into a small animal model. The presence of calcium ions in the local environment naturally induces gel formation, ensuring the scaffold remains in place. The outcome of this example is highly favorable, with significantly enhanced neovascularization observed around the injection site. This improvement in blood vessel formation is achieved with minimal swelling or foreign-body reactions, highlighting the biocompatibility and effectiveness of the dermal filler for tissue regeneration.
[0064] These illustrative embodiments showcase the potential of the injectable nano-bioactive scaffold in promoting tissue regeneration across various applications, from dental to cosmetic treatments. The sustained release of growth factors and the biocompatible nature of the scaffold components underscore its innovative and therapeutic advantages.
[0065] While the foregoing has described what may be considered to be the best mode and / or other examples, it is understood that various modifications may be made therein and that the subject matter disclosed herein may be implemented in various forms and examples, and that the teachings may be applied in numerous applications, only some of which have been described herein. It is intended by the following claims to claim any and all applications, modifications and variations that fall within the true scope of the present teachings.
[0066] Unless otherwise stated, all measurements, values, ratings, positions, magnitudes, sizes, and other specifications that are set forth in this specification, including in the claims that follow, are approximate, not exact. They are intended to have a reasonable range that is consistent with the functions to which they relate and with what is customary in the art to which they pertain.
[0067] The scope of protection is limited solely by the claims that now follow. That scope is intended and should be interpreted to be as broad as is consistent with the ordinary meaning of the language that is used in the claims when interpreted in light of this specification and the prosecution history that follows and to encompass all structural and functional equivalents.
[0068] Except as stated immediately above, nothing that has been stated or illustrated is intended or should be interpreted to cause a dedication of any component, step, feature, object, benefit, advantage, or equivalent to the public, regardless of whether it is or is not recited in the claims.
[0069] It will be understood that the terms and expressions used herein have the ordinary meaning as is accorded to such terms and expressions with respect to their corresponding respective spaces of inquiry and study except where specific meanings have otherwise been set forth herein. Relational terms such as first and second and the like may be used solely to distinguish one entity or action from another without necessarily requiring or implying any actual such relationship or order between such entities or actions. The terms “comprises,” “comprising,” or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent tosuch process, method, article, or apparatus. An element proceeded by “a” or “an” does not, without further constraints, preclude the existence of additional identical elements in the process, method, article, or apparatus that comprises the element.
[0070] The Abstract of the Disclosure is provided to allow the reader to quickly ascertain the nature of the technical disclosure. It is submitted with the understanding that it will not be used to interpret or limit the scope or meaning of the claims. In addition, in the foregoing Detailed Description, it can be seen that various features are grouped together in various implementations. This is for purposes of streamlining the disclosure, and is not to be interpreted as reflecting an intention that the claimed implementations require more features than are expressly recited in each claim. Rather, as the following claims reflect, inventive subject matter lies in less than all features of a single disclosed implementation. Thus, the following claims are hereby incorporated into the Detailed Description, with each claim standing on its own as a separately claimed subject matter.
[0071] While various implementations have been described, the description is intended to be exemplary, rather than limiting and it will be apparent to those of ordinary skill in the art that many more implementations and implementations are possible that are within the scope of the implementations. Although many possible combinations of features are shown in the accompanying figures and discussed in this detailed description, many other combinations of the disclosed features are possible. Any feature of any implementation may be used in combination with or substituted for any other feature or element in any other implementation unless specifically restricted. Therefore, it will be understood that any of the features shown and / or discussed in the present disclosure may be implemented together in any suitable combination. Accordingly, the implementations are not to be restricted except in light of the attached claims and their equivalents. Also, various modifications and changes may be made within the scope of the attached claims.
Claims
What is claimed is:
1. An injectable nano-bioactive scaffold for controlled release of growth factors and tissue regeneration, the injectable nano-bioactive scaffold comprising:a biocompatible hydrogel base, the bio compatible hydrogel base comprising: an amount of methacrylated hyaluronic acid (HA -MA), the amount of methacrylated hyaluronic acid (HA -MA) being in a range between 1 % (w / v) and 3% (w / v);an amount of carbodiimide -mediated hyaluronic acid;an amount of partially deacetylated chitosan with positively charged amino groups, the amount of partially deacetylated chitosan being in a range between 0.5% (w / w) and 2% (w / w);an amount of alginate, the amount of alginate being in a range between 2% (w / w) and 4% (w / w); andself-assembling peptides, the self-assembling peptides comprising an amount of RADA 16 peptide, the amount of RADA 16 peptide being in a range between 0.2% (w / v) and 0.7% (w / v);chemical crosslinkers, the chemical crosslinkers comprising:an amount of l-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC);an amount of N-Hydroxy succinimide (NHS); andan amount of genipin; andnano-structured reinforcements, the nano-structured reinforcements comprising:an amount of mesoporous silica nanoparticles, pore sizes of the amount of mesoporous silica nanoparticles being in a range between 2 nanometers and 50nanometers, the amount of mesoporous silica nanoparticles being in a range between 0.1 (mg / ml) and 0.3 (mg / ml);an amount of electrospun collagen nanofibers, the amount of electrospun collagen nanofibers being in a range between 0.4 (w / w) and 0.6 (w / w);an amount of gelatin nanofibers;Poly(lactic-co-glycolic acid) (PLGA) nanofibers;an amount of silver nanoparticles;an amount of copper nanoparticles; andan amount of zinc oxide nanoparticles;growth factors, the growth factors comprising:an amount of fibroblast growth factor (FGF);an amount of liposomal vascular endothelial growth factor (VEGF), the amount of liposomal vascular endothelial growth factor (VEGF) being in a range between 0.5 (pg / mL) and 1.5 (pg / mL); andan amount of transforming growth factor-beta (TGF-P).
2. The injectable nano-bioactive scaffold of claim 1, wherein:the amount of methacrylated hyaluronic acid (HA -MA) is 2% (w / v);the amount of partially deacetylated chitosan is 1% (w / w);the amount of alginate is 3% (w / w);the amount of RADA 16 peptide is 0.5% (w / v);pore sizes of the amount of mesoporous silica nanoparticles are 25 nanometers; the amount of mesoporous silica nanoparticles is 0.2 (mg / ml);the amount of electrospun collagen nanofibers is 0.5 (w / w); andthe amount of liposomal vascular endothelial growth factor (VEGF) is 1 (pg / mL).
3. A method for preparing an injectable nano-bioactive scaffold for controlled release of growth factors and tissue regeneration, the method comprising:preparing a biocompatible hydrogel base by mixing an amount of methacrylated hyaluronic acid (HA-MA), an amount of carbodiimide-mediated hyaluronic acid, an amount of partially deacetylated chitosan with positively charged amino groups, an amount of alginate, an amount of RADA16 peptide, an amount of l-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), an amount of N-Hydroxysuccinimide (NHS), and an amount of genipin, the amount of methacrylated hyaluronic acid (HA-MA) being between 1% (w / v) and 3% (w / v), the amount of partially deacetylated chitosan being between 0.5% (w / w) and 2% (w / w), the amount of alginate being in a range between 2% (w / w) and 4% (w / w), the amount of RADA 16 peptide being in a range between 0.2% (w / v) and 0.7% (w / v);adding nano-structured reinforcements to the biocompatible hydrogel base, the nanostructured reinforcements comprising:an amount of mesoporous silica nanoparticles, pore sizes of the amount of mesoporous silica nanoparticles being in a range between 2 nanometers and 50 nanometers, the amount of mesoporous silica nanoparticles being in a range between 0.1 (mg / ml) and 0.3 (mg / ml);an amount of electrospun collagen nanofibers, the amount of electrospun collagen nanofibers being in a range between 0.4 (w / w) and 0.6 (w / w);an amount of gelatin nanofibers;Poly(lactic-co-glycolic acid) (PLGA) nanofibers;an amount of silver nanoparticles;an amount of copper nanoparticles; andan amount of zinc oxide nanoparticles; andadding growth factors to the biocompatible hydrogel base, the growth factors comprising:an amount of fibroblast growth factor (FGF);an amount of liposomal vascular endothelial growth factor (VEGF), the amount of liposomal vascular endothelial growth factor (VEGF) being in a range between 0.5 (pg / mL) and 1.5 (pg / mL); andan amount of transforming growth factor-beta (TGF-P).
4. The method of claim 3, wherein:the amount of methacrylated hyaluronic acid (HA-MA) is 2% (w / v);the amount of partially deacetylated chitosan is 1% (w / w);the amount of alginate is 3% (w / w);the amount of RADA 16 peptide is 0.5% (w / v);pore sizes of the amount of mesoporous silica nanoparticles are 25 nanometers; the amount of mesoporous silica nanoparticles is 0.2 (mg / ml);the amount of electrospun collagen nanofibers is 0.5 (w / w); and the amount of liposomal vascular endothelial growth factor (VEGF) is 1 (pg / mL).
5. An injectable hydrogel for gingival regeneration, the injectable hydrogel comprising:an amount of methacrylated hyaluronic acid (HA-MA), the amount of methacrylated hyaluronic acid (HA-MA) being 2% (w / v);an amount of partially deacetylated chitosan with positively charged amino groups, the amount of partially deacetylated chitosan being 1% (w / w);an amount of mesoporous silica nanoparticles, pore sizes of the amount of mesoporous silica nanoparticles being in a range between 2 nanometers and 50 nanometers, the amount of mesoporous silica nanoparticles being in a range between 0.1 (mg / ml) and 0.3 (mg / ml); andan amount of RADA16 peptide, the amount of RADA16 peptide being 0.5% (w / v).