Osteoporotic fractures typically exhibit delayed healing due to impaired cell recruitment, chronic inflammation, and disrupted neurovascular signaling. Sensory nerve signaling plays a crucial role in fracture repair, and its deficiency is a significant factor leading to delayed healing. Addressing these deficiencies is crucial to overcoming the challenges associated with delayed bone repair in osteoporosis. In this study, a smart composite hydrogel (denoted as OCS-MPC) was synthesized by embedding CGRP-functionalized polydopamine-coated MXene nanosheets (MXene/PDA/CGRP) into boronic acid-modified oxidized hyaluronic acid-crosslinked carboxymethyl chitosan (OHA-PBA/CMCS) hydrogel loaded with SDF-1. OCS-MPC hydrogel enables the controlled release of SDF-1 and CGRP, aiming to promote early callus formation and late-stage callus remodeling in osteoporotic fractures. Due to dynamic crosslinking via imine and borate ester bonds, OCS-MPC exhibits rapid gelation, injectability, and self-healing properties. In vitro experiments demonstrated excellent osteogenic, angiogenic, and neurogenic properties of OCS-MPC hydrogel. In vivo studies using an osteoporotic femoral fracture model showed that OCS-MPC hydrogel enhanced MSCs recruitment via the SDF-1/CXCR4 signaling axis, significantly improving callus formation in the early stages of fracture repair. Additionally, OCS-MPC hydrogel significantly promoted callus mineralization and remodeling in the later stages of osteoporotic fracture healing through enhancing CGRP signaling. Immunofluorescence analysis further confirmed increased expression of TUBB3, CGRP, and CD31, indicating successful regeneration of the neurovascular network. These findings highlight the potential of OCS-MPC hydrogel in addressing both early and late-stage challenges of osteoporotic fracture healing, providing a promising therapeutic strategy for enhancing bone regeneration in osteoporotic patients.

To improve the efficiency of hyaluronic acid production by Streptococcus zooepidemicus, the growth medium was optimized with a pipeline involving a deep learning (DL) algorithm. To train the DL model, the initial training dataset (OA01-18) was designed with the L18 orthogonal array, and hyaluronic acid (HA) was produced in small-scale cultures in deepwell plates. The range of HA production was 0.09-1.39 g/L under these conditions. In searching for the optimal medium composition, 54 candidate optimized media (OM01-54) were proposed by the system. According to the confirming culture experiment, the best production of HA (1.66 g/L) was achieved with OM30. During confirmation in a stirred-tank reactor, the volumetric production of HA in OA30 was larger than that in the control medium. In fed batch culture, HA accumulated to 5.13 and 9.96 g/Linitial volume after 10 and 30 h in culture, respectively. To avoid the suppression of HA production by the high viscosity of the medium conferred by HA, repeated batch culture with OM30 was performed by replacing 90 % of the broth volume approximately every 6 h. As a result, 21.4 g of HA was produced in 46 h, and productivity reached 0.465 g/Linitial volume/h.

In today's emergency medical field, rapid hemostasis and wound healing technologies are of paramount importance. However, traditional methods, although effective, have limitations such as slow hemostasis, susceptibility to infection, and unsuitability for irregular wounds. To address these issues, this study combined methacrylated hyaluronic acid (HAMA) with zinc chondroitin sulfate (CSZn) to successfully develop a novel sprayable photocurable hydrogel, CSZn@HAMA. Material characterization confirmed that CSZn was effectively loaded into HAMA, while retaining HAMA's photocurable and sprayable properties. This allows the CSZn@HAMA hydrogel to rapidly solidify and form a tight protective film over the wound after spraying. Further cell experiments demonstrated that this hydrogel has significant anti-inflammatory effects and can effectively promote collagen production and angiogenesis. Therefore, CSZn@HAMA has emerged as a promising biomaterial for wound management in emergency medical care.

The process of face aging is characterized by various signs, including nasolabial folds, sagging and hollowing, all of which worsen with age. In some subjects, this phenomenon is exacerbated by sun exposure, bad diet, genetic factor, pollution, etc. This remains a great concern as it impacts physiologically and psychologically on patient quality of life. The intradermal solution based on bio-fermentative HA is indicated for correction of skin damages including rhytidosis, photoaging and skin dehydration. The present clinical investigation was designed for obtaining further clinical safety and efficacy data for the SKIN R intradermal solution for the treatment of skin damages. The efficacy of the treatments was assessed by measuring the pH, assessment of sebometry, and hydrometry, Global Aesthetic Improvement Scale and Subject satisfaction. All 15 screened and enrolled subjects were treated with the investigational device at least once. All subjects who were assessed had a neck photo taken at visits 1 and 2. The subjects' judgment of appearance after treatment changed with time, however, by the termination of the study on Day 60, 33.3% of subjects still considered their appearance very much improved, and 46,6% still considered their appearance much improved. The assessment of "satisfaction with treatment" was very high by the majority of subjects. No major adverse event was recorded. In conclusion, SKIN R is safe and well-tolerated and is effective in the treatment of skin damage.

Bone regeneration is a highly complex process involving the coordinated interaction between osteogenic stem cells, the extracellular matrix (ECM), and osteoinductive signals, which are often challenged by bacterial interference. While bone prostheses incorporating growth factors such as bone morphogenetic proteins have been commercially successful, the therapeutic use of recombinant growth factors can lead to significant adverse clinical outcomes. Here, we present a photo-curable layered double hydroxide (LDH)-composite hydrogel, designed to incorporate multiple functionalities for bone regeneration without the need for exogenous growth factors. The photo-curable hyaluronic acid (HA) hydrogel features a porous microstructure, biocompatibility, precise application, and adaptability to irregular bone defects. Incorporating LDH not only enhances osteogenic signals but also provides antibacterial activity, reducing the risk of infection and promoting a more favorable environment for bone regeneration. The combination of photo-curable HA with the functional 2D-nanomaterial LDH, renowned for its ability to intercalate therapeutic molecules, results in a hydrogel scaffold that emulates the osteoconductive traits of bone ECM. Additionally, the controlled release of the osteoinductive agent simvastatin via LDH augments bone healing through stimulation of the Wnt/β-catenin pathway. This nanoengineered HA-based hydrogel demonstrates significant potential as a multifunctional bone prosthesis, offering a promising, growth factor-free solution for enhanced bone regeneration.

Diabetic wounds healing is often severely slowed by hyperglycemia, elevated oxidative stress, bacterial infections, and persistent inflammation. This review focuses on the development of hydrogels derived from carbohydrate polymer and protein to facilitate diabetic wound healing. We discuss the primary sources of cellulose, chitosan, hyaluronic acid, sodium alginate, collagen, and gelatin along with their advantages in the preparation of hydrogels. Based on the microenvironment of diabetic wounds, i.e., hyperglycemia, increased oxidative stress, and persistent inflammation, the application of multifunctional hydrogels in promoting diabetic wounds, including stimulus responsiveness, injection self-healing, antibacterial, antioxidant, anti-inflammatory, and synergistic effects, is discussed. We address the main challenges and future perspectives of multifunctional hydrogels based on carbohydrate polymer and protein in the treatment of diabetic wounds.

Recently, various adhesive materials have been developed for versatile biomedical applications owing to their rapid and strong adhesion to tissues in water-rich environments. One such example is gallol-containing chitosan (CHI-G), which contains multiple gallol and amine groups in its backbone. However, the practical application of CHI-G alone is limited owing to its intrinsic mechanical strength and undesirable immune responses. In this study, we developed Ca2+ ions- and hyaluronic acid-containing CHI-G (CHC) patches to prevent anastomotic leakage and accelerate wound healing. CHC hydrogel patches showed increased elastic modulus values (809.4 ± 181.7 Pa) compared to that of CHI-G hydrogel patches (137.0 ± 16.3 Pa). In addition, the bursting pressure (78.2 ± 3.5 mmHg) of CHC hydrogel patch-applied porcine intestine was far higher than those of the control (4.13 ± 0.4 mmHg) and HA groups (14.5 ± 2.5 mmHg). CHC hydrogel patches showed suitable mechanical properties and biocompatibility for wound-sealing and dressing applications in water-rich environments. Notably, the CHC hydrogel patch-applied wound healing animal model exhibited a healing rate of over 90 % at 14 days post-surgery, notably higher than that of the control group (76 %). These findings suggest that CHC patches have considerable potential as effective wound dressings and sealing materials.

Self-repair of articular cartilage defects is a significant challenge that can be addressed using drug-infused hydrogels, which improve injection convenience and provide immediate in situ adhesion. In this study, we developed a hydrogel incorporating Lipo@Kartogenin (KGN) and the cationic functional peptide SKPPGTSS (SKP) linked to aldehyde-based methacrylated hyaluronic acid (AHAMA). The innovative injectable hydrogel responded to visible light, allowing cross-linking under white light (∼30 s) and effective adhesion to cartilage tissue. The hydrogel facilitated the sustained release of KGN and SKP over approximately 28 days as it degraded, thereby promoting the homing and differentiation of endogenous bone marrow-derived mesenchymal stem cells (BMSCs). Transcriptome sequencing showed that Smad4 expression and activation of the TGF-β signaling pathway are fundamental to these processes. In vivo studies in Sprague-Dawley (SD) rats showed that this hydrogel supports optimal hyaline cartilage regeneration within 8 weeks. In conclusion, our visible light-responsive adhesive co-delivery hydrogel effectively recruited native BMSCs to cartilage lesion sites and provided an environment conducive to their differentiation into cartilage, thereby facilitating effective cartilage regeneration. This innovation represents a novel approach to the clinical repair of cartilage defects.

Stem cell therapy has revolutionized neurodegenerative disease treatment by presenting promising medical applications. Despite their potential, stem cell therapy remains constrained by various limitations, including low differentiation efficiency, difficulties in guiding differentiation, proliferation control, shorter half-life of growth factors, experimental reproducibility, etc. The cellular niche environment is pivotal in effective differentiation of stem cells. Neural regeneration ventures require biomaterial-based 3D scaffolds to simulate in-vivo tissue to solve the niche environment problem. Recent breakthroughs in neural regeneration have led to the development of a biomimetic scaffolds made of Hyaluronic acid (HA) and collagen (COL) that imitate the CNS's extracellular matrix (ECM) for better neural regeneration and repair. HA and COL based scaffold creates a favourable microenvironment for cellular migration, proliferation and survival of the embedded stem cells and promotes neural regeneration. HA regulates cellular activities while COL contributes in healing CNS injuries. Therefore, the utilization of HA-COL based scaffolds is appropriate for regulating cellular responses and behaviour for neural regeneration. This review investigates the synergy between HA and COL in the context of neural-specific applications for repair, regeneration, and recovery as well as augmentation of bioactivity through fabrication techniques such as 3D bioprinting, electrospinning, etc. for neural tissue regeneration.

Chronic inflammation at bone defect sites can impede regenerative processes, but local immune responses can be adjusted to promote healing. Regulating the osteoimmune microenvironment, particularly through macrophage polarization, has become a key focus in bone regeneration research. While bone implants are crucial for addressing significant bone defects, they are often recognized by the immune system as foreign, triggering inflammation that leads to bone resorption and implant issues like fibrous encapsulation and aseptic loosening. Developing osteoimmunomodulatory implants offers a promising approach to transforming destructive inflammation into healing processes, enhancing implant integration and bone regeneration. This review explores strategies based on tuning the physicochemical attributes and chemical composition of materials in engineering osteoimmunomodulatory and pro-regenerative bone implants.

Background: Periodontitis is a prevalent inflammatory condition that destroys periodontal tissues. Scaling and root planing (SRP) is the gold standard for non-surgical treatment; however, its efficacy may be limited in cases with complex dental issues. This umbrella review aims to evaluate the effectiveness of hyaluronic acid (HA) as an adjunct to scaling and root planing (SRP) in enhancing clinical outcomes for periodontitis management. Methods: A comprehensive review of five systematic reviews, including meta-analyses where available, was conducted to synthesize evidence on the adjunctive use of HA with SRP. The studies were evaluated using the AMSTAR-2 quality assessment tool to determine methodological rigor. Data on clinical parameters such as probing depth (PD), clinical attachment level (CAL), bleeding on probing (BOP), gingival index (GI), and plaque index (PI) were extracted and analyzed. Results: The findings indicate that HA supplementation leads to moderate improvements in PD, CAL, BOP, GI, and PI compared to SRP alone. Notable reductions in PD and gains in CAL were observed, with some meta-analyses showing statistically significant benefits. However, the heterogeneity in HA concentrations (0.2-1.4%), application methods, treatment frequencies, and follow-up durations (1 week to 12 months) limits definitive conclusions. Additionally, HA did not significantly affect the reduction in P. gingivalis prevalence. Conclusions: The use of HA in conjunction with SRP shows promise in enhancing the efficacy of non-surgical periodontal therapy. However, the heterogeneity in the quality and methodologies of the studies indicates the necessity for high-quality, standardized randomized controlled trials to establish clear clinical guidelines for the application of HA in the treatment of periodontitis.

This study aimed to investigate the osteogenic function of polyetheretherketone (PEEK) scaffolds modified with bone morphogenetic protein 2 (BMP2) and its possibility for orbital fracture repair. The 3D-printed PEEK sheets were combined with BMP2-loaded hyaluronic acid hydrogel (HAH) to fabricate PEEK-BMP2-HAH composite scaffolds. Bone marrow mesenchymal stem cells (BMSCs) were seeded onto PEEK or PEEK-BMP2-HAH scaffolds. Cell adhesion and cell proliferation were measured by transmission electron microscopy and CCK-8 assay. Alkaline phosphatase (ALP) chromogenic, alizarine red S staining, and PCR analysis of Runt-related transcription factor 2 (Runx2), collagen-I (Col-I), Osterix, and osteopontin (OPN) were performed to assess osteogenic activity. The rat orbital fracture defect model is proposed for evaluating the biocompatibility, osteogenic integration, and functional recovery of PEEK orbital implants. Compared with PEEK, cell adhesion and cell proliferation were increased in PEEK-BMP2-HAH scaffolds. ALP activity and mineralized nodule formation were increased in PEEK-BMP2-HAH scaffolds than that in PEEK the mRNA expression of Runx2, Osterix, Col-I and OPN was increased on PEEK-BMP2-HAH scaffolds than that on PEEK at 14 d of osteogenic induction. Besides, a bone defect animal model revealed that BMP2-HAH-modified PEEK scaffolds could effectively facilitate the repair of the orbital bone defect, with increased expression of OPN and Runx2. BMP2-loaded HAH effectively increased adhesion, proliferation, and osteogenic differentiation of BMSCs on PEEK. PEEK-BMP2-HAH scaffolds are expected to become new materials for orbital fracture repair.

Diabetic patients are associated with a series of post extraction complications, such as delayed healing, greater risk of infections, persistent pain, dry socket and delayed bone formation. There is paucity of studies which indicate the influence of glycemic index and antibiotic prophylaxis in prevention of complications after minor surgical procedures. Various adjuncts such as hydrogels, curcumin and platelet gels are used in the extraction socket to augment healing, minimize complications and promote bone regeneration.

To assess the effect of hyaluronic acid gel with and without metronidazole on wound healing in post extraction sockets of diabetic patients.

A double blind randomized controlled study was conducted at FDS, RUAS, Bengaluru, India. Diabetic patients indicated for simple extraction of mandibular molars were randomly divided into two groups and prescribed oral metronidazole 1 h prior to extraction. After extraction, 1% hyaluronic acid gel was placed in the sockets of patients in Group A and Group B received 1% hyaluronic acid gel with 5% metronidazole. Soft tissue healing was assessed after one week using wound healing index and photographs of the socket with AutoCAD program. Pain was assessed by VAS. Hard tissue healing was evaluated radiologically using CBCT scans taken immediately after extraction and after one month and analyzed in the 3D slicer software. Pain was assessed by VAS, number of rescue analgesics, complications if any.

There was no statistically significant difference in hard and soft tissue healing and pain scores between the two groups. However, it was statistically significant between the two-time intervals within each group.

In patients with short term glycemic control, use of a single dose of oral metronidazole prior to extraction and placement of 1% hyaluronic acid gel in the extraction socket resulted in uneventful healing with evidence of bone formation at one month. Addition of 5% metronidazole to the gel seems to have no added advantage.

Not registered.

The increasing incidence of bone diseases has driven research towards Bone Tissue Engineering (BTE), an innovative discipline that uses biomaterials to develop three-dimensional (3D) scaffolds capable of mimicking the natural environment of bone tissue. Traditional approaches relying on two-dimensional (2D) models have exhibited significant limitations in simulating cellular interactions and the complexity of the bone microenvironment. In response to these challenges, 3D models such as organoids and cellular spheroids have emerged as effective tools for studying bone regeneration. Adult mesenchymal stem cells have proven crucial in this context, as they can differentiate into osteoblasts and contribute to bone tissue repair. Furthermore, the integration of composite biomaterials has shown substantial potential in enhancing bone healing. Advanced technologies like microfluidics offer additional opportunities to create controlled environments for cell culture, facilitating more detailed studies on bone regeneration. These advancements represent a fundamental step forward in the treatment of bone pathologies and the promotion of skeletal health. In this review, we report on the evolution of in vitro culture models applied to the study of bone healing/regrowth, starting from 2 to 3D cultures and microfluids. The different methodologies of in vitro model generation, cells and biomaterials are presented and discussed.

Bone regeneration is limited and generally requires external intervention to promote effective repair. Autografts, allografts, and xenografts as traditional methods for addressing bone defects have been widely utilized, their clinical applicability is limited due to their respective disadvantages. Fortunately, functional polysaccharide hydrogels have gained significant attention in bone regeneration due to their exceptional drug-loading capacity, biocompatibility, and ease of chemical modification. They also provide an optimal microenvironment for bone repair and regeneration. This review provides an overview of various functional polysaccharide hydrogels derived from biocompatible materials, focusing on their applications in intelligent delivery systems, bone tissue regeneration, and cartilage defect repair. Particularly, the incorporation of bioactive molecules into the design of functional polysaccharide hydrogels has been shown to significantly enhance bone regeneration. Additionally, this review emphasizes the preparation methods for functional polysaccharide hydrogels and associated the bone healing mechanisms. Finally, the limitations and future prospects of functional polysaccharide hydrogels are thoroughly evaluated.

Extracellular matrix (ECM) derived from mesenchymal stem cells regulates antioxidant properties and bone metabolism by providing a favorable extracellular microenvironment. However, its functional role and molecular mechanism in mitochondrial function regulation and aged bone regeneration remain insufficiently elucidated. This proteomic analysis has revealed a greater abundance of proteins supporting mitochondrial function in the young ECM (Y-ECM) secreted by young bone marrow-derived mesenchymal stem cells (BMMSCs) compared to the aged ECM (A-ECM). Further studies demonstrate that Y-ECM significantly rejuvenates mitochondrial energy metabolism in adult BMMSCs (A-BMMSCs) through the promotion of mitochondrial respiratory functions and amelioration of oxidative stress. A-BMMSCs cultured on Y-ECM exhibited enhanced multi-lineage differentiation potentials in vitro and ectopic bone formation in vivo. Mechanistically, silencing of silent information regulator type 3 (SIRT3) gene abolished the protective impact of Y-ECM on A-BMMSCs. Notably, a novel composite biomaterial combining hyaluronic acid methacrylate hydrogel microspheres with Y-ECM is developed, which yielded substantial improvements in the healing of bone defects in an aged rat model. Collectively, these findings underscore the pivotal role of Y-ECM in maintaining mitochondrial redox homeostasis and present a promising therapeutic strategy for the repair of aged bone defects.

Objective: to evaluate the efficacy, safety, and cost-effectiveness of intra-articular hyaluronic acid (IAHA) in treating osteoarthritis (OA), considering innovations in formulations, comparative outcomes, and variability in guidelines. This review aims to synthesize evidence supporting the role of IAHA in multimodal treatment strategies. Materials and Methods: A general, narrative, umbrella review of systematic reviews and meta-analyses was conducted. Clinical practice recommendations and guidelines for IAHA use were also reviewed and evaluated. A comprehensive search was conducted across the main medical data sources. Inclusion criteria focused on studies evaluating the efficacy, safety, and impact of IAHA. Key outcomes included pain reduction (e.g., WOMAC, VAS), functional improvement, safety, and cost-effectiveness. Results: IAHA showed moderate efficacy in pain relief and functional improvement, especially in early-to-moderate OA. The results indicate that hybrid formulations and combination therapies show better clinical outcomes, with expanded efficacy and potential chondroprotection. However, heterogeneity between studies was noted, reflecting variability in patient populations and intervention protocols. International guidelines varied significantly, with some opposing routine use (e.g., AAOS, NICE) and others endorsing IAHA more or less conditionally (e.g., ESCEO, OARSI). Conclusions: IAHA remains a treatment modality in the arsenal of selected populations of people with OA, especially for early and moderate disease. High-quality, standardized studies are still needed to refine IAHA's role and establish personalized guidelines for individual patients. A concerted effort to harmonize global recommendations and economic strategies, such as tiered pricing, can increase equitable access and optimize IAHA's integration of multimodal treatment for OA.

Bone tissue engineering (BTE) seeks to overcome the limitations of traditional bone repair methods, such as autografts and allografts, which are often limited by availability, donor-site morbidity, immune rejection, and infection risks. Recent advancements have highlighted the potential of spheroids or microtissues as building blocks for BTE. This study aimed to investigate the osteogenic differentiation of spheroids formed from human periosteum-derived cells (hPDCs) and bone marrow-derived mesenchymal stromal cells (hBMSCs) in a hyaluronic acid methacrylate (HAMA) matrix, using encapsulation and extrusion bioprinting methods. Results showed significant morphological changes, high viability, and osteogenic differentiation of spheroids from hPDCs or hBMSCs in three-dimensional HAMA environments. Notably, hPDC spheroids demonstrated higher mineralization capabilities and superior hydrogel colonization than hBMSC spheroids. These findings reveal the potential of HAMA bioink containing hPDC spheroids to produce mineralized bone grafts using a bioprinting approach.

Purslane (Portulaca oleracea L.) with heat-clearing and detoxicating, anti-inflammatory and resolving swelling, relieving itching and astringing function, has remarkable efficacy for acute eczema. However, most of the clinical applications of purslane are freshly prepared decoction, not as easy to apply as cream, because the decoction is easy to breed bacteria and easy to oxidize. Here, based on the theory of Chinese medicines compatibility, we made a purslane-tannic acid hydrogel (PL-HATA) by simple methods under mild conditions to solve the drawbacks of easy oxidation and inconvenience of use of Purslane. The antimicrobial activity of PL-HATA hydrogel can exert an excellent antimicrobial effect, reducing the flora on the skin of acute eczema and further relieving the symptoms of acute eczema. At the same time, it creates a normal reactive oxygen species (ROS) microenvironment for acute eczema and promotes recovery from acute eczema. It also improves the symptoms of acute eczema by promoting cell proliferation and migration. Importantly, it resulted in improved skin lesion scores, scratching behavior, eosinophil infiltration, swelling and inflammation levels, immune homeostasis, and histopathological changes in rats with acute eczema. Besides, HATA hydrogel is not only suitable for Purslane's decocted metabolites but also for Purslane's freshly squeezed metabolites. This purslane application protocol solved the drawbacks of Purslane's decoction, improved its storage stability and convenience of use, which is the key issue to further promote its clinical application.

Osteoarthritis (OA) presents a significant therapeutic challenge, with few options for preserving joint cartilage and repairing associated tissue damage. Inflammation is a pivotal factor in OA-induced cartilage deterioration and synovial inflammation. Recently, exosomes derived from human umbilical cord mesenchymal stem cells (HucMSCs) have gained recognition as a promising noncellular therapeutic modality, but their use is hindered by the challenge of harvesting a sufficient number of exosomes with effective therapeutic efficacy. Given that HucMSCs are highly sensitive to microenvironmental signals, we hypothesized that priming HucMSCs within a proinflammatory environment would increase the number of exosomes secreted with enhanced anti-inflammatory properties. Subsequent miRNA profiling and pathway analysis confirmed that interleukin-1 beta (IL-1β)-induced exosomes (C-Exos) exert positive effects through miRNA regulation and signaling pathway modulation. In vitro experiments revealed that C-Exos enhance chondrocyte functionality and cartilage matrix production, as well as macrophage polarization, thereby enhancing cartilage repair. C-Exos were encapsulated in hyaluronic acid hydrogel microspheres (HMs) to ensure sustained release, leading to substantial improvements in the inflammatory microenvironment and cartilage regeneration in a rat OA model. This study outlines a strategy to tailor exosome cargo for anti-inflammatory and cartilage regenerative purposes, with the functionalized HMs demonstrating potential for OA treatment.

There is ongoing research for biomedical applications of polyvinyl alcohol (PVA)-based hydrogels; however, the execution of this has not yet been achieved at an appropriate level for commercialization. Advanced perception is necessary for the design and synthesis of suitable materials, such as PVA-based hydrogel for biomedical applications. Among polymers, PVA-based hydrogel has drawn great interest in biomedical applications owing to their attractive potential with characteristics such as good biocompatibility, great mechanical strength, and apposite water content. By designing the suitable synthesis approach and investigating the hydrogel structure, PVA-based hydrogels can attain superb cytocompatibility, flexibility, and antimicrobial activities, signifying that it is a good candidate for tissue engineering and regenerative medicine, drug delivery, wound dressing, contact lenses, and other fields. In this review, we highlight the current progresses on the synthesis of PVA-based hydrogels for biomedical applications explaining their diverse usage across a variety of areas. We explain numerous synthesis techniques and related phenomena for biomedical applications based on these materials. This review may stipulate a wide reference for future acumens of PVA-based hydrogel materials for their extensive applications in biomedical fields.

Bone defects resulting from congenital anomalies and trauma pose significant clinical challenges for orthopedics surgeries, where bone tissue engineering (BTE) aims to address these challenges by repairing defects that fail to heal spontaneously. Despite numerous advances, BTE still faces several challenges, i.e., difficulties in detecting and tracking implanted cells, high costs, and regulatory approval hurdles. Biomaterials promise to revolutionize bone grafting procedures, heralding a new era of regenerative medicine and advancing patient outcomes worldwide. Specifically, novel bioactive biomaterials have been developed that promote cell adhesion, proliferation, and differentiation and have osteoconductive and osteoinductive characteristics, stimulating tissue regeneration and repair, particularly in complex skeletal defects caused by trauma, degeneration, and neoplasia. A wide array of biological therapeutics for bone regeneration have emerged, drawing from the diverse spectrum of gene therapy, immune cell interactions, and RNA molecules. This review will provide insights into the current state and potential of future strategies for bone regeneration.

Background/Objectives: Tooth extraction induces significant alveolar ridge dimensional changes and soft tissue modifications, often leading to challenges in implant placement or conventional prosthetic rehabilitation. Alveolar Ridge Preservation (ARP) strategies aim to mitigate post-extraction resorption of the alveolar ridge, enhancing both the quality and quantity of bone and soft tissue during healing. Hyaluronic acid (HYA) has emerged as a promising biological agent for ARP due to its osteoinductive, antimicrobial, and anti-inflammatory properties. However, the effects of HYA in ARP remain inconsistently reported. This study aims to assess current clinical and preclinical evidence regarding the biological effects of HYA and its application in ARP. Additionally, it evaluates HYA's impact-alone or in combination with other products-on hard and soft tissue dimensional changes, early wound healing, and implant success rates. Methods: A comprehensive electronic literature search was conducted, and studies meeting the inclusion criteria were critically evaluated. Relevant data were extracted from the final selection of articles. Results: Thirteen publications were evaluated. Some studies reported a significantly improved newly formed bone following ARP with intra-socket HYA application as a single approach (p = 0.004). Combining HYA with a bone graft and a free palatal graft resulted in significantly greater amounts of newly formed and mature bone, reduced clinical bone width changes, lower radiographic crestal bone loss (p < 0.01), and diminished radiological volumetric and linear bone resorption (p = 0.018). Short-term follow-up data indicated improved soft tissue healing associated with HYA-based ARP. While HYA appears to have a protective effect on ridge dimensional changes in ARP, other studies reported no significant differences in radiographic bone dimensional changes or soft tissue improvement. Conclusions: The addition of HYA to bone grafts may enhance some ARP outcomes. However, the variability in outcomes and methodologies across the evaluated studies precludes drawing definitive clinical conclusions. Further robust research is needed to clarify HYA's role in ARP. With respect to clinical significance enhancing the understanding of ARP management strategies and their effects on post-extraction sockets empowers clinicians to make more informed decisions. The knowledge of HYA effects facilitates the selection of personalized ARP approaches tailored to optimize outcomes for subsequent interventions.

In recent years, hyaluronic acid (HA) has attracted increasing attention as a promising biomaterial for the development of drug delivery systems. Due to its unique properties, such as high biocompatibility, low toxicity, and modifiability, HA is becoming a basis for the creation of targeted drug delivery systems, especially in the field of oncology. Receptors for HA overexpressed in subpopulations of cancer cells, and one of them, CD44, is recognized as a molecular marker for cancer stem cells. This review examines the role of HA and its receptors in health and tumors and analyzes existing HA-based delivery systems and their use in various types of cancer. The development of new HA-based drug delivery systems will bring new opportunities and challenges to anti-cancer therapy.

Amphibians are enjoyable globally for their culinary value and are increasingly considered alternative protein sources. However, the skin of edible amphibians, especially giant salamanders, is often discarded without much thought. However, this underutilized resource holds significant potential for yielding valuable proteins and bioactive peptides (BPs). These peptides, such as brevinins, bombesins, dermaseptins, esculentins, magainins, temporins, tigerinins, and salamandrins, possess a wide range of biological activities, including antioxidant, antimicrobial, anticancer, and antidiabetic properties. This review provides a comprehensive analysis of the various BPs derived from giant salamander skin or secretions and their associated biological functions. Furthermore, it examines the nutritional composition of giant salamanders, their production status, and the challenges surrounding the use of their skin and secretions. This review also explores the potential applications of these BPs in the food and biomedical industries, particularly as multifunctional food additives, dietary supplements, and drug delivery agents.

Managing segmental mandibular defects remains challenging, requiring a multidisciplinary approach despite the remarkable progress in mandibular reconstruction plates, finite element methods, computer-aided design and manufacturing techniques, and novel surgical procedures. Complex surgeries require a comprehensive approach, as using only reconstruction plates or tissue scaffolds may not be adequate for optimal results. The limitations of the treatment options should be investigated towards a patient-specific trend to provide shorter surgery time, better healing, and lower costs. Integrated hybrid scaffold systems are promising in improving mechanical properties and facilitating healing. By combining different materials and structures, hybrid scaffolds can provide enhanced support and stability to the tissue regeneration process, leading to better patient outcomes. The use of such systems represents a significant advancement in tissue engineering and a wide range of medical procedures.

A head and neck computed tomography (CT) data of a patient with odontogenic myxoma was used for creating a three-dimensional (3D) mandible model. Virtual osteotomies were performed to create a segmental defect model, including the angulus mandibulae region. The first mandibular reconstruction plate was designed. Finite elemental analyses (FEA) and topology optimizations were performed to create two different reconstruction plates for different treatment scenarios. The FEA were performed for the resulting two plates to assess their biomechanical performance. To provide osteoconductive and osteoinductive properties a scaffold was designed using the defect area. A biomimetic Tricalcium phosphate-Polycaprolactone (TCP-PCL) hybrid bone scaffold enhanced with Hyaluronic acid dipping was manufactured.

The results of the in-silico analysis indicate that the designed reconstruction plates possess robust biomechanical performance and demonstrate remarkable stability under the most rigorous masticatory activities. Using the Voronoi pattern decreased the mass by %37 without losing endurance. Using reconstruction plates and hybrid scaffolds exhibits promising potential for clinical applications, subject to further in vivo and clinical studies.

Various factors can contribute to bone damage or loss, presenting challenges for bone regeneration. Our study explores the potential clinical applications of two processed forms of Wharton's jelly of the human umbilical cord for treating bone loss. Wharton's jelly from fresh umbilical cords underwent two distinct processes: (1) frozen Wharton's jelly (WJF), preserved with cryoprotective agents, and (2) decellularized Wharton's jelly matrix (WJD), prepared only via lyophilization without cryoprotectants. Both WJD and WJF are rich in collagen, hyaluronan, and polysaccharide proteins. Notably, WJD exhibited a porous structure lacking nuclei from human umbilical cord mesenchymal stem cells, unlike WJF. In direct contact experiments, WJD stimulated osteoblast migration, enhanced osteoblast maturation, and promoted calcium deposition for bone formation when administered to cultured rat osteoblasts. Furthermore, in transwell co-culture experiments, both WJD and WJF increased the rat osteoblast expression of RUNX2 and OPN genes, elevated alkaline phosphatase levels, and enhanced extracellular calcium precipitation, indicating their role in osteoblast maturation and new bone formation. Hyaluronic acid, one of the ingredients from WJD and WJF, was identified as a key component triggering osteogenesis. In vivo experiments involved creating circular bone defects in the calvarias of rats, where WJD and WJF were separately implanted and monitored over five months using micro-computerized tomography. Our results demonstrated that both WJD and WJF enhanced angiogenesis, collagen formation, osteoblast maturation, and bone growth within the bone defects. In summary, WJD and WJF, natural biomaterials with biocompatibility and nontoxicity, act not only as effective scaffolds but also promote osteoblast adhesion and differentiation, and accelerate osteogenesis.

Hyaluronic acid (HA) has multiple biological activities which are closely related to its molecular weight. In the present study, the photoelectrocatalytic method was established for HA degradation and the influences of bias potentials, H2O2 additions and reaction times on the degradation results were investigated to optimize the reaction condition. Moreover, a series of analysis methods, such as FT-IR and NMR were used to analyze chemical compositions of the degradation products, revealing that photoelectrocatalytic degradation did not damage the structural blocks of HA obviously. Then 11 oligosaccharides with polymerization degrees from 2 to 8 in the degradation products were identified by mass spectroscopy and their reducing ends were all GlcA or AraA. In addition, in the photoelectrocatalytic degradation of HA, ·OH were identified as the most influential among the produced free radicals, and it could be proposed that ·OH specifically targeted the anomeric carbon of GlcA, resulting in the disaggregation of polysaccharides chain. Furthermore, the results of in vitro fermentation with fecal microbiota demonstrated that HA and its degradation products regulated microbiota structure discriminately, indicating their possible different outcomes as nutritional supplements and agents.

Osteoporosis, a prevalent skeletal disorder characterized by diminished bone density, compromised microstructure, and heightened fracture susceptibility, poses a growing public health concern exacerbated by aging demographics. Polysaccharides-based materials, derived from a diverse range of sources, exhibit exceptional biocompatibility. They possess a structure similar to the extracellular matrix, which can enhance cell adhesion in vivo, and demonstrate superior biological activity compared to artificial materials. This study delved into an in-depth examination of the various biomaterials and polysaccharide families associated with the treatment of osteoporosis. This article elucidates the benefits and attributes of polysaccharide-based materials in contrast to current clinical treatment modalities, delineating how these materials address prevalent challenges in the clinical management of osteoporosis. An overview of the prospective applications of polysaccharide-based materials in the future is also provided, as well as outlines the challenges that should be addressed prior to the clinical implementation of such materials.

Polymers have become essential in advancing bone tissue engineering, providing adaptable bone healing and regeneration solutions. Their biocompatibility and biodegradability make them ideal candidates for creating scaffolds that mimic the body's natural extracellular matrix (ECM). However, significant challenges remain, including degradation by-products, insufficient mechanical strength, and suboptimal cellular interactions. This article addresses these challenges by evaluating the performance of polymers like poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), and polylactic acid (PLA) in scaffold development. It also explores recent innovations, such as intelligent polymers, bioprinting, and the integration of bioactive molecules to enhance scaffold efficacy. We propose that overcoming current limitations requires a combination of novel biomaterials, advanced fabrication techniques, and tailored regulatory strategies. The future potential of polymer-based scaffolds in personalised regenerative medicine is discussed, focusing on their clinical applicability.

The present study aims to determine whether the brain-derived neurotrophic factor (BDNF)/high-molecular-weight hyaluronic acid (HMW-HA) complex could regenerate bone around implants lost due to peri-implantitis.

Dogs had their three premolars extracted, and three implants were placed on each side. After osseointegration, 3-0 silk threads were ligated around the healing abutment for 12 weeks. Implants were classified into four groups-no treatment (control group), non-surgical debridement (debridement group), non-surgical debridement with application of HMW-HA (HMW-HA group), and non-surgical debridement with application of BDNF/HMW-HA complex (BDNF/HMW-HA group). Probing pocket depth (PPD), attachment level (AL), and bleeding on probing (BOP) were recorded before and 12 weeks after each treatment. Standardized intraoral radiographs were obtained, and histological analysis was conducted.

The bone level on radiographs significantly improved (median -0.15 mm, IQR -0.31 to 0.10) only in the BDNF/HMW-HA group, while changes in PPD and AL were similar to those in other groups. The BOP positivity rate decreased in the debridement and BDNF/HMW-HA groups. Unlike images of the other groups, histological images of the BDNF/HMW-HA group showed no epithelial migration toward the tip of the implant. Inflammatory cell infiltration was reduced compared with that in the other groups. New bone was observed around the implants only in the BDNF/HMW-HA group.

The BDNF/HMW-HA complex appears to promote bone regeneration when combined with non-surgical debridement for peri-implantitis.

Understanding how mechanical stimulation from exercise influences cellular responses during tissue repair could enhance therapeutic strategies. We explored zebrafish caudal fin regeneration to study exercise impacts on a robust model of tissue regeneration. We used a swim tunnel to determine that exercise initiated during but not after blastema establishment impaired fin regeneration, including of the bony ray skeleton. Long-term tracking of fluorescently labeled cell lineages showed exercise disrupted blastemal mesenchyme formation. Transcriptomic profiling and section staining indicated exercise reduced an extracellular matrix (ECM) gene expression program, including for hyaluronic acid (HA) synthesis. Like exercise, HA synthesis inhibition or blastemal HA depletion disrupted blastema formation. We considered if injury-upregulated HA establishes a pro-regenerative environment facilitating mechanotransduction. HA density across the blastema correlated with nuclear localization of the mechanotransducer Yes-associated protein (Yap). Further, exercise loading or reducing HA decreased nuclear Yap and cell proliferation. We conclude early exercise during fin regeneration disrupts expression of an HA-rich ECM supporting blastema expansion. These results highlight the interface between mechanotransduction and ECM as consideration for timing exercise interventions and developing regenerative therapies.

Controlled exercise promotes healing and recovery from severe skeletal injuries. However, properly timed interventions are essential to promote recovery and prevent further damage. We use zebrafish caudal fin regeneration to mechanistically study exercise impacts on a naturally robust and experimentally accessible model of tissue repair. We link detrimental early exercise effects during fin regeneration to impaired ECM synthesis, mechanotransduction, and cell proliferation. These insights could explain the value of delaying the onset of physical therapy and suggest pursuing therapies that maintain ECM integrity for regenerative rehabilitation.

Osteomyelitis caused by drug-resistant pathogens is one of the most important medical challenges due to high rates of mortality and morbidity, and limited therapeutical options. The application of novel nano-scaffolds loaded with antibiotics has widely been studied and extensively evaluated for in vitro and in vivo inhibition of pathogens, regenerating damaged bone tissue, and increasing bone cell proliferation. The treatment of bone infections using the local osteogenic scaffolds loaded with antimicrobial agents may efficiently overcome the problems of the systemic use of antimicrobial agents and provide a controlled release and sufficient local levels of antibiotics in the infected sites. The present study reviewed various nano-scaffolds delivery systems of antimicrobial drugs evaluated to treat osteomyelitis. Nano-scaffolds offer promising approaches because they simulate natural tissue regeneration in terms of their mechanical, structural, and sometimes chemical properties. The potential of several nano-scaffolds prepared by natural polymers such as silk, collagen, gelatin, fibrinogen, chitosan, cellulose, hyaluronic, alginate, and synthetic compounds such as polylactic acid, polyglycolic acid, poly (lactic acid-co-glycolic acid), poly-ɛ-caprolactone have been studied for usage as drug delivery systems of antimicrobial agents to treat osteomyelitis. In addition to incorporated antimicrobial agents and the content of scaffolds, the physical and chemical characteristics of the prepared delivery systems are a determining factor in their effectiveness in treating osteomyelitis.

Large osseous defects resulting from trauma, tumor resection, or fracture render the inherent ability of the body to repair inadequate and necessitate the use of bone grafts to facilitate the recovery of both form and function of the bony defect sites. In the United States alone, a large number of bone graft procedures are performed yearly, making it an essential area of investigation and research. Synthetic grafts represent a potential alterative to autografts due to their patient-specific customizability, but currently lack widespread acceptance in the clinical space. Early in their development, non-autologous bone grafts composed of metals such as stainless steel and titanium alloys were favorable due to their biocompatibility, resistance to corrosion, mechanical strength, and durability. However, since their inception, bioceramics have also evolved as viable alternatives. This review aims to present an overview of the fundamental prerequisites for tissue engineering devices using bioceramics as well as to provide a comprehensive account of their historical usage and significant advancements over time. This review includes a summary of commonly used manufacturing techniques and an evaluation of their use as drug carriers and bioactive coatings-for therapeutic ion/drug release, and potential avenues to further enhance hard tissue regeneration.

In addition to transmitting and carrying genetic information, RNA plays an important abiotic role in the world of nanomaterials. RNA is a natural polyanionic biomacromolecule, and its ability to promote osteogenesis by binding with other inorganic materials as an osteogenic induction agent was discovered only recently. However, whether it can promote osseointegration on implants has not been reported. Here, we investigated the effect of the RNA-containing coating materials on peri-implant osseointegration. Total RNA extracted from rat muscle tissue was used as an osteogenic induction agent, and hyaluronic acid (HA) was used to maintain its negative charge. In simulated body fluids (SBF), in vitro studies demonstrated that the resulting material encouraged calcium salt deposition. Cytological experiments showed that the RNA-containing coating induced greater cell adhesion and osteogenic differentiation in comparison to the control. The results of animal experiments showed that the RNA-containing coating had osteoinductive and bone conduction activities, which are beneficial for bone formation and osseointegration. Therefore, the RNA-containing coatings are useful for the surface modification of titanium implants to promote osseointegration.

The effective regeneration of bone/cartilage defects remains a significant clinical challenge, causing irreversible damage to millions annually.Conventional therapies such as autologous or artificial bone grafting often yield unsatisfactory outcomes, emphasizing the urgent need for innovative treatment methods. Biomaterial-based strategies, including hydrogels and active scaffolds, have shown potential in promoting bone/cartilage regeneration. Among them, injectable hydrogels have garnered substantial attention in recent years on account of their minimal invasiveness, shape adaptation, and controlled spatiotemporal release. This review systematically discusses the synthesis of injectable hydrogels, bioinspired approaches-covering microenvironment, structural, compositional, and bioactive component-inspired strategies-and their applications in various bone/cartilage disease models, highlighting bone/cartilage regeneration from an innovative perspective of bioinspired design. Taken together, bioinspired injectable hydrogels offer promising and feasible solutions for promoting bone/cartilage regeneration, ultimately laying the foundations for clinical applications. Furthermore, insights into further prospective directions for AI in injectable hydrogels screening and organoid construction are provided.

Cyclic olefin copolymer (COC) has recently emerged as an attractive material in biomedical fields for its high purity, excellent stability and chemical resistance, particularly in applications of microfluidic chips, prefilled syringes and bone regeneration. However, the high hydrophobicity of COC has inhibited the adhesion of cells and biological macromolecules, such as proteins, etc., significantly limiting its broader applications. In this study, we propose a new method to modify COC surfaces by sequential coating with polydopamine (PDA) followed by hyaluronic acid (HA) or O-carboxymethyl chitosan (CMC), while comparing the impacts of the positively charged HA and negatively charged CMC on protein adsorption and cell adhesion. FTIR and XPS measurements confirmed the successful modification on COC films, resulting in surfaces with highly increased hydrophilicity, anti-oxidative properties, and improved protein adsorption. Moreover, negatively charged HA, with signal transduction capabilities showed a greater effect in promoting cell adhesion. Thus, we present a straightforward strategy for enhancing the hydrophilicity of COC surfaces, offering new insights into COC modification and potential biomedical applications.

The incorporation of silver nanoparticles (AgNPs) into alginate-gelatin (Alg-Gel) hydrogels can enhance the properties of these materials for bone regeneration applications, due to the antimicrobial properties of AgNPs and non-cytotoxic concentrations, osteoinductive properties, and regulation of stem cell proliferation and differentiation. Here, the hydrogel formulation included 2% (w/v) sodium alginate, 4 µg/mL AgNPs, and 2.5% (w/v) gelatin. AgNPs were synthesized using a 2% (w/v) aqueous extract of roasted green tea with silver nitrate. The aqueous extract of roasted green tea for AgNP synthesis was characterized using HPLC and UHPLC-ESI-QTOF-MS/MS, and antioxidant capacity was measured in Trolox equivalents (TE) from 4 to 20 nmol/well concentrations. Stem cells from human exfoliated deciduous tooth cells were used for differentiation assays including positive (SHEDs/hydrogel with AgNPs) and negative controls (hydrogel without AgNPs). FTIR was used for hydrogel chemical characterization. Statistical analysis (p < 0.05, ANOVA) confirmed significant findings. Roasted green tea extract contained caffeine (most abundant), (-)-Gallocatechin, gallic acid, and various catechins. XRD analysis revealed FCC structure, TEM showed quasispheroidal AgNPs (19.85 ± 3 nm), and UV-Vis indicated a plasmon surface of 418 nm. This integration of nanotechnology and biomaterials shows promise for addressing bone tissue loss in clinical and surgical settings.

In photodynamic therapy (PDT), reactive oxygen species (ROS) are key products that induce cell death, and increasing amount of ROS is a crucial way to enhance PDT efficacy. However, the generated ROS stimulates the transient receptor potential vanilloid 1 channel (TRPV1), which can be activated in the pain pathway and then exacerbate pain. Herein, we utilized arginine-glycine-aspartate (RGD) peptide-modified liposomes for encapsulation Chlorin e6 (Ce6) and capsazepine (Cz), a receptor antagonist of TRPV1, to prepare drug-loaded liposomes, RLCC. Soluble hyaluronic acid microneedle arrays (MNs), which possess sufficient skin penetration capability and excellent biosafety, was applied for in situ delivery of RLCC. With the aid of RGD peptides, the efficiency of intracellular liposomal uptake and the dispersion of drugs in tumor after delivery by MNs were significantly enhanced, showcasing tremendous potential for improving the PDT efficacy. Besides, through the analysis of sciatic nerve signals in mice during PDT, RLCC demonstrated remarkable effectiveness in alleviating pain by significantly reducing nerve impulses. Hence, RLCC demonstrated outstanding effectiveness in PDT and effectively alleviated the associated pain. Overall, this research highlights the potential of utilizing MNs for the in situ delivery of RLCC, facilitating effective PDT while addressing the issue of pain during the treatment.

Ridge preservation is essential to restore alveolar ridge volume and to enhance esthetic and functional outcomes for dental implants. The addition of hyaluronic acid to allogeneic bone substitute materials might enhance these outcomes. This clinical study evaluated the efficacy of ridge preservation after tooth extraction using granular allografts with and without hyaluronic acid addition.

In this retrospective study, 40 patients with compromised extraction sockets were enrolled. Among them, 19 received particulate allogeneic bone substitutes (Allo), 21 received allogeneic bone substitutes with hyaluronic acid (AlloHya). Vertical and horizontal graft stability, graft shrinkage rate, and bone mineral density were assessed using radiographic measurements on CBCT scans conducted before tooth extraction, directly after ridge preservation and after four months. Patients were followed up 12 months post-implantation.

Vertical height loss after 4 months was significantly greater in the Allo group (-0.82 ± 0.95 mm) compared to the AlloHya group (-0.19 ± 0.51 mm; p = 0.011). Graft shrinkage rate was 16.9 ± 11.5% (Allo) and 10.3 ± 7.7% (AlloHya) (p = 0.038). After four months, average bone density was significantly higher in the AlloHya compared to the Allo group (p = 0.004). Nearly all implants (39 out of 40) were classified as "Success" according to the ICOI scheme, with no differences in implant quality between the two study groups.

Improved graft stability, reduced resorption, and increased bone density were observed in hyaluronic acid-enriched allografts compared to pure allografts. Adding hyaluronic acid to allogeneic bone grafts significantly enhanced outcomes in ridge preservation.

Cementum is a vital component of periodontium, yet its regeneration remains a challenge. Pentraxin 3 (PTX3) is a multifunctional glycoprotein involved in extracellular matrix remodeling and bone metabolism regulation. However, the role of PTX3 in cementum formation and cementoblast differentiation has not been elucidated. In this study, we initially observed an increase in PTX3 expression during cementum formation and cementoblast differentiation. Then, overexpression of PTX3 significantly enhanced the differentiation ability of cementoblasts. While conversely, PTX3 knockdown exerted an inhibitory effect. Moreover, in Ptx3-deficient mice, we found that cementum formation was hampered. Furthermore, we confirmed the presence of PTX3 within the hyaluronan (HA) matrix, thereby activating the ITGB1/FAK/YAP1 signaling pathway. Notably, inhibiting any component of this signaling pathway partially reduced the ability of PTX3 to promote cementoblast differentiation. In conclusion, our study indicated that PTX3 promotes cementum formation and cementoblast differentiation, which is partially dependent on the HA/ITGB1/FAK/YAP1 signaling pathway. This research will contribute to our understanding of cementum regeneration after destruction.