Growth Factors to Enhance Nerve Regeneration: Approaching Clinical Translation.

Following nerve injury, growth factors (GFs) are transiently upregulated in injured neurons, proliferating Schwann cells, and denervated muscle and skin. They act on these same cells and tissues to promote nerve regeneration and end-organ reinnervation. Consequently, much attention has been focused on developing GF-based therapeutics. A major barrier to clinical translation of GFs is their short half-life. To provide sustained GF treatment to the affected nerve, muscle, and skin in a safe and practical manner, engineered drug delivery systems are needed. This review highlights recent advancements in GF-based therapeutics and discusses the remaining hurdles for clinical translation.

Biological strategies supporting the orthopaedic treatment / Biologiczne wspomaganie leczenia ortopedycznego.

Damage to the musculoskeletal system significantly impairs mobility and quality of life, limiting everyday activities. For a successful orthopedic treatment, anatomical, physiological and biomechanical factors must be taken into account as they all influence tissue healing. It is therefore of crucial importance to support traditional treatment with biological therapies, as they facilitate the regeneration of the tissue microarchitecture. Such orthobiologics work at the cellular level (orthobiologics rich in mesenchymal cells or growth factors) or at the tissue level (matrices for repairing e.g. cartilage). In this review, we describe the most frequently used orthobiologics rich in mesenchymal cells (bone marrow, autologous adipose tissue, tenocytes, umbilical cord, urine and bursa) and growth factors, presenting the molecular basis of their functioning and their clinical effectiveness.

Autologous Concentrate Growth Factor for the Treatment of Endo-Perio Lesion - A Case Report.

INTRODUCTION: The success of a combined periodontal and endodontic lesion depends on the elimination of both these disease processes. In the case of a combined endo-perio lesion, endodontic therapy results in healing of the endodontic component of involvement, while the prognosis of teeth would finally depend on the healing of the periodontal structure. TREATMENT: This case report evaluates the efficacy of autologous fibrin glue and bone graft, that is, sticky bone in the management of bone defects associated with endo-perio lesion. The endo-perio lesion is first treated endodontically, followed by periodontal therapy. Conclusion: The patient was kept on follow-up for 9 months, and satisfactory results in terms of bone fill and reduction in pocket depth were obtained. TAKEAWAY LESSONS: The sticky bone enhances regeneration in treatment of endo-perio lesions.

The current status of various preclinical therapeutic approaches for tendon repair.

Tendons are fibroblastic structures that link muscle and bone. There are two kinds of tendon injuries, including acute and chronic. Each form of injury or deterioration can result in significant pain and loss of tendon function. The recovery of tendon damage is a complex and time-consuming recovery process. Depending on the anatomical location of the tendon tissue, the clinical outcomes are not the same. The healing of the wound process is divided into three stages that overlap: inflammation, proliferation, and tissue remodeling. Furthermore, the curing tendon has a high re-tear rate. Faced with the challenges, tendon injury management is still a clinical issue that must be resolved as soon as possible. Several newer directions and breakthroughs in tendon recovery have emerged in recent years. This article describes tendon injury and summarizes recent advances in tendon recovery, along with stem cell therapy, gene therapy, Platelet-rich plasma remedy, growth factors, drug treatment, and tissue engineering. Despite the recent fast-growing research in tendon recovery treatment, still, none of them translated to the clinical setting. This review provides a detailed overview of tendon injuries and potential preclinical approaches for treating tendon injuries.

[Autologous platelet concentrates in regenerative dentistry - A narrative literature review. Part I: Theoretical and legal aspects of the PR(G)F application].

The use of autologous platelet concentrates (APC) such as platelet-rich fibrin (PRF) and/or plasma rich in growth factors (PRGF®) is considered an established treatment modality in re-generative dentistry. The possibility of delivering growth factors over aclinically relevant time of several days seems particularly interesting in the context of wound healing.The growing body of evidence in the field of APC requires a continuous and actual knowledge of the literature for being able to make evidence-based treatment recommendations with a realistic assessment of possible advantages of this technology.PR(G)F can be applied in solid or liquid form, pure or in combination with other biomaterials. Both appear to be reasonable, depending on the clinical indication and/or desired treatment outcomes. Because of the many different factors that can affect the PR(G)F products final characteristics, a basic understanding of these parameters is desirable for choosing the most suitable product and/or optimizing its clinical application. This review aims to provide an over-view of relevant theoretical, practical, legal and biologic aspects of APCs.

A randomized controlled clinical trial of concentrated growth factor combined with sodium hyaluronate in the treatment of temporomandibular joint osteoarthritis.

OBJECTIVE: To investigate the effect of concentrated growth factor (CGF) combined with sodium hyaluronate (SH) on temporomandibular joint osteoarthritis (TMJOA). METHODS: Sixty patients with TMJOA who were diagnosed by cone-beam computed tomography (CBCT) between March 2020 and March 2023 at the Stomatological Hospital of Xi'an Jiaotong University were randomly divided into a control group (n = 30) and an experimental group (n = 30). The patients in the experimental group were treated with CGF + SH, and those in the control group were treated with SH only. The visual analogue scale (VAS) score indicating pain in the temporomandibular joint (TMJ) area; the Helkimo Clinical Dysfunction Index (Di); and changes in condylar CBCT at the first visit and 2 weeks, 3 months and 6 months after treatment were recorded. The CBCT data of the patients in the experimental and control groups were collected, and the three-dimensional CBCT image sequences were imported into Mimics Medical 19.0 software in DICOM format for condylar reconstruction. RESULTS: The VAS scores at 2 weeks, 3 months and 6 months after treatment were significantly lower in the experimental group than in the control group (P < 0.05), and the pain in the experimental group was significantly relieved. The Di was significantly lower in the experimental group than in the control group (P < 0.05), and the clinical function of the TMJ improved. After treatment, the CBCT score was significantly lower in the experimental group than in the control group (P < 0.05), and the condylar bone cortex was obviously repaired. Observation of the condylar bone cortex by three-dimensional reconstruction showed the same results as those obtained by CBCT. CONCLUSION: CGF combined with SH is effective in the treatment of TMJOA and can improve muscle pain, TMJ pain, Impaired TMJ function, Impaired range of movement, Pain on movement of the mandible and promote bone repair. THE REGISTRATION NUMBER (TRN): ChiCTR2400082712. THE DATE OF REGISTRATION: April 5, 2024.

Treatment of Odontogenic Maxillary Sinusitis with the Use of Growth Factors in Advanced Platelet-Rich Fibrin for Immediate Closure of Oro-Antral Communication: A Case Report.

Chronic odontogenic maxillary sinusitis (COMS), a prolonged inflammation of the maxillary sinus lasting over 12 weeks, is often a result of periapical lesions, marginal periodontitis, and complications like oro-antral communication (OAC) and fistula (OAF). OAC, commonly emerging post-teeth extraction in the lateral maxilla, lacks documented treatments using advanced platelet-rich fibrin (A-PRF). This study evaluates A-PRF's efficacy in treating COMS and immediately sealing extensive OAC. A case of a 28-year-old male with COMS linked to a periapical lesion and supernumerary molars is presented. Treatment involved extracting specific teeth while preserving adjacent ones and using A-PRF for immediate OAC closure. A-PRF, enriched with growth factors, was pivotal in healing, showcasing enhanced tissue regeneration, pain reduction, and faster recovery. The findings suggest A-PRF as an effective adjunct in treating extensive OAC and COMS, proposing its inclusion in standard treatment protocols. This study underscores A-PRF's potential in improving outcomes for patients with COMS and related complications.

How effective are concentrated growth factor and injectable platelets in reducing complications following impacted third molar surgery?

OBJECTIVES: This study examined the impact of injectable platelet-rich fibrin (iPRF) and concentrated growth factor on postoperative pain, edema, trismus, and quality of life in impacted mandibular third molar surgery. The primary aim of this study was to minimize common sequelae following third molar surgery by using iPRF and concentrated growth factor. The secondary objective was to compare the postoperative effects of these products. METHOD AND MATERIALS: This study represents a single-center, randomized prospective clinical trial conducted at the Ordu University Faculty of Dentistry. It involved patients who underwent third molar surgery for various reasons between July and October 2022. The predictor variables were the use of concentrated growth factor and i-PRF. They were categorized as concentrated growth factor, i-PRF, and control groups. The outcome variables include pain levels and analgesic consumption measured on a visual analog scale, distances between predetermined anatomical points, maximum mouth opening capacity, and data from the postoperative symptom severity (PoSSe) scale. Some statistical tests were performed with a 95% confidence interval, which was considered significant. RESULTS: Total analgesic use was notably lower in the concentrated growth factor group (P = .044). Concentrated growth factor and iPRF outperformed the control group in all edema measurements by postoperative day 7 (tragus-pogonion, lateral canthus-angulus, tragus-commissura; P < .05). Concentrated growth factor significantly reduced trismus on days 2 and 7. Quality of life was notably higher in the concentrated growth factor group than in the control group (P = .026), although iPRF group differences were not significant. CONCLUSION: The results indicate that concentrated growth factor has a limited impact on postoperative pain, but significantly reduces edema, trismus, and enhances quality of life. The iPRF group experienced positive effects on pain, edema, and trismus, although the statistically significant differences observed with concentrated growth factor highlight its potential for use instead of iPRF after third molar surgery. An increased sample size is essential for more comprehensive results.

Neuroprotective effect of apelin-13 and other apelin forms-a review.

Neurodegenerative diseases, which occur when neurons begin to deteriorate, affect millions of people worldwide. These age-related disorders are becoming more common partly because the elderly population has increased in recent years. While no treatments are accessible, every year an increasing number of therapeutic and supportive options become available. Various substances that may have neuroprotective effects are currently being researched. One of them is apelin. This review aims to illustrate the results of research on the neuroprotective effect of apelin amino acid oligopeptide which binds to the apelin receptor and exhibits neuroprotective effects in the central nervous system. The collected data indicate that apelin can protect the central nervous system against injury by several mechanisms. More studies are needed to thoroughly investigate the potential neuroprotective effects of this peptide in neurodegenerative diseases and various other types of brain damage.

The Effect of Connective Tissue Graft Compared to Concentrated Growth Factor Graft on Buccal Peri-Implant Gingival Thickness: A 12-month Randomized Controlled Clinical Trial.

BACKGROUND: Attached gingival phenotype has a crucial impact on the implant's durability and its future success. PURPOSE: This study aims to measure and compare buccal peri-implant gingival thickness following grafting with connective tissue graft (CTG) and the concentrated growth factor (CGF) graft. STUDY DESIGN, SETTING, SAMPLE: This is a split-mouth designed randomized controlled clinical study in which a total of 20 aged 18 to 55 have bilateral missing teeth in the maxillary premolar region with less than 2 mm of healthy peri-implant gingival thickness. Patients were excluded if they were smokers, had poor oral hygiene, had uncontrolled widespread periodontal disease, or had a history of radiation treatment. The same surgical protocol was followed for each study participant, where an independent blinded medical practitioner assigned the first stage side to be treated with CTG, while the second stage side with CGF 2 weeks later. EXPOSURE VARIABLE: The primary exposure variable of this study was the gingival grafting technique; CTG or CGF. OUTCOME VARIABLE: The primary outcome variable was the buccal peri-implant gingival thickness. Gingival thickness was measured at six different times; immediately before the procedure (T0), after 30 days (T1), after 45 days (T2), after 3 months (T3), after 6 months (T4), and after 12 months (T5). COVARIATES: The covariates were age, sex general health, and periodontal status. ANALYSIS: The statistical analysis; repeated measures analysis of variance test was used to compare the gingival thickness between the studied follow-up times within each group. The level of significance was set at ≤ 0.05. RESULTS: The sample was composed of 40 treatment sites of 20 patients. The mean age of the sample was 32 years and 45% were male. The mean gingival thickness value of the CTG group was 1.62 mm with a (standard deviation = 0.18) compared to 1.28 mm for the CGF group with (standard deviation = 0.20) and an overall P value (0.001) at T5. CONCLUSIONS AND RELEVANCE: CTG showed to have better gingival thickness than CGF in managing peri-implant buccal gingival thickness deficiency.

Discrete Mechanistic Target of Rapamycin Signaling Pathways, Stem Cells, and Therapeutic Targets.

The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that functions via its discrete binding partners to form two multiprotein complexes, mTOR complex 1 and 2 (mTORC1 and mTORC2). Rapamycin-sensitive mTORC1, which regulates protein synthesis and cell growth, is tightly controlled by PI3K/Akt and is nutrient-/growth factor-sensitive. In the brain, mTORC1 is also sensitive to neurotransmitter signaling. mTORC2, which is modulated by growth factor signaling, is associated with ribosomes and is insensitive to rapamycin. mTOR regulates stem cell and cancer stem cell characteristics. Aberrant Akt/mTOR activation is involved in multistep tumorigenesis in a variety of cancers, thereby suggesting that the inhibition of mTOR may have therapeutic potential. Rapamycin and its analogues, known as rapalogues, suppress mTOR activity through an allosteric mechanism that only suppresses mTORC1, albeit incompletely. ATP-catalytic binding site inhibitors are designed to inhibit both complexes. This review describes the regulation of mTOR and the targeting of its complexes in the treatment of cancers, such as glioblastoma, and their stem cells.

Improving Diabetic Wound-Healing Outcomes With Topical Growth Factor Therapies.

CONTEXT: Diabetes mellitus is associated with morbid complications such as diabetic foot ulcers (DFUs) that may lead to amputations or mortality if not managed adequately. OBJECTIVE: New adjunctive interventions to treat diabetic wounds include topical biologics and growth factors. This study aims to evaluate their efficacy in improving wound-healing outcomes and safety. METHODS: Comprehensive database searches of MEDLINE via PubMed, EMBASE, and Cochrane were performed from inception to December 2022. Three independent researchers selected the studies. Randomized controlled trials that compared the use of a topical biologic growth factor-containing regimen to other biologics or standard of care (SOC) were included. This review followed PRISMA guidelines. Risk of bias analysis was performed using the Jadad scale. Network meta-analysis was performed. Treatments were grouped into common nodes based on the type of biologic agent. Primary outcomes of interest were healing rate and time to wound closure. Secondary outcomes included wound infection, serious adverse events (AEs), and amputation rate. RESULTS: Human umbilical cord (HUC) was associated with the highest cure, followed by recombinant human epidermal growth factor (hEGF). A significantly greater reduction in the time to cure DFUs was seen in HUC, hEGF, and fibroblast growth factor (FGF). There was a significantly lower risk of AEs when platelet-rich plasma (PRP) was administered. CONCLUSION: HUC, hEGF, and FGF are promising topical biologics with statistically significant primary outcomes compared to SOC, while PRP is effective in reducing ulcer-related AEs. HUC has been found to be the most effective in terms of cure rate and a reduction in time to cure.

Encapsulation of the growth factor neurotrophin-3 in heparinised poloxamer hydrogel stabilises bioactivity and provides sustained release.

Poloxamer-based hydrogels show promise to stabilise and sustain the delivery of growth factors in tissue engineering applications, such as following spinal cord injury. Typically, growth factors such as neurotrophin-3 (NT-3) degrade rapidly in solution. Similarly, poloxamer hydrogels also degrade readily and are, therefore, only capable of sustaining the release of a payload over a small number of days. In this study, we focused on optimising a hydrogel formulation, incorporating both poloxamer 188 and 407, for the sustained delivery of bioactive NT-3. Hyaluronic acid blended into the hydrogels significantly reduced the degradation of the gel. We identified an optimal hydrogel composition consisting of 20 % w/w poloxamer 407, 5 % w/w poloxamer 188, 0.6 % w/w NaCl, and 1.5 % w/w hyaluronic acid. Heparin was chemically bound to the poloxamer chains to enhance interactions between the hydrogel and the growth factor. The unmodified and heparin-modified hydrogels exhibited sustained release of NT-3 for 28 days while preserving the bioactivity of NT-3. Moreover, these hydrogels demonstrated excellent cytocompatibility and had properties suitable for injection into the intrathecal space, underscoring their suitability as a growth factor delivery system. The findings presented here contribute valuable insights to the development of effective delivery strategies for therapeutic growth factors for tissue engineering approaches, including the treatment of spinal cord injury.

The therapeutic effect of concentrated growth factor gel on skin wounds with bone or tendon exposure.

Treatment of soft tissue wounds with bone or tendon exposure remains a tough clinical challenge for surgeons. The current clinical approaches include various types of flap reconstruction and artificial dermis grafting as well as negative pressure wound therapy (NPWT), which are time-consuming and often result in graft failure or significant scarring. Concentrated growth factor (CGF) is a novel blood extract that contains many growth factors, platelets and fibrin to promote an orderly healing process. However, few reports have focused on wounds with bone or tendon exposure. We present a limited series and two specific cases of skin wound with bone or tendon exposed that received surgical debridement followed by CGF treatment. CGF appeared to facilitate wound closure effectively and also reduced scar formation. Our findings provide a novel therapeutic option for refractory wounds with bone or tendon exposure.

Blockage of mechanosensitive Piezo1 channel alleviates the severity of experimental malaria-associated acute lung injury.

BACKGROUND: Malaria-associated acute lung injury (MA-ALI) is a well-recognized clinical complication of severe, complicated malaria that is partly driven by sequestrations of infected red blood cells (iRBCs) on lung postcapillary induced impaired blood flow. In earlier studies the mechanosensitive Piezo1 channel emerged as a regulator of mechanical stimuli, but the function and underlying mechanism of Piezo1 impacting MA-ALI severity via sensing the impaired pulmonary blood flow are still not fully elucidated. Thus, the present study aimed to explore the role of Piezo1 in the severity of murine MA-ALI. METHODS: Here, we utilized a widely accepted murine model of MA-ALI using C57BL/6 mice with Plasmodium berghei ANKA infection and then added a Piezo1 inhibitor (GsMTx4) to the model. The iRBC-stimulated Raw264.7 macrophages in vitro were also targeted with GsMTx4 to further explore the potential mechanism. RESULTS: Our data showed an elevation in the expression of Piezo1 and number of Piezo1+-CD68+ macrophages in lung tissues of the experimental MA-ALI mice. Compared to the infected control mice, the blockage of Piezo1 with GsMTx4 dramatically improved the survival rate but decreased body weight loss, peripheral blood parasitemia/lung parasite burden, experimental cerebral malaria incidence, total protein concentrations in bronchoalveolar lavage fluid, lung wet/dry weight ratio, vascular leakage, pathological damage, apoptosis and number of CD68+ and CD86+ macrophages in lung tissues. This was accompanied by a dramatic increase in the number of CD206+ macrophages (M2-like subtype), upregulation of anti-inflammatory cytokines (e.g. IL-4 and IL-10) and downregulation of pro-inflammatory cytokines (e.g. TNF-α and IL-1ß). In addition, GsMTx4 treatment remarkably decreased pulmonary intracellular iron accumulation, protein level of 4-HNE (an activator of ferroptosis) and the number of CD68+-Piezo1+ and CD68+-4-HNE+ macrophages but significantly increased protein levels of GPX4 (an inhibitor of ferroptosis) in experimental MA-ALI mice. Similarly, in vitro study showed that the administration of GsMTx4 led to a remarkable elevation in the mRNA levels of CD206, IL-4, IL-10 and GPX-4 but to a substantial decline in CD86, TNF-α, IL-1ß and 4-HNE in the iRBC-stimulated Raw264.7 cells. CONCLUSIONS: Our findings indicated that blockage of Piezo1 with GsMTx4 alleviated the severity of experimental MA-ALI in mice partly by triggering pulmonary macrophage M2 polarization and subsequent anti-inflammatory responses but inhibited apoptosis and ferroptosis in lung tissue. Our data suggested that targeting Piezo1 in macrophages could be a promising therapeutic strategy for treating MA-ALI.

Recent Achievements in the Development of Biomaterials Improved with Platelet Concentrates for Soft and Hard Tissue Engineering Applications.

Platelet concentrates such as platelet-rich plasma, platelet-rich fibrin or concentrated growth factors are cost-effective autologous preparations containing various growth factors, including platelet-derived growth factor, transforming growth factor ß, insulin-like growth factor 1 and vascular endothelial growth factor. For this reason, they are often used in regenerative medicine to treat wounds, nerve damage as well as cartilage and bone defects. Unfortunately, after administration, these preparations release growth factors very quickly, which lose their activity rapidly. As a consequence, this results in the need to repeat the therapy, which is associated with additional pain and discomfort for the patient. Recent research shows that combining platelet concentrates with biomaterials overcomes this problem because growth factors are released in a more sustainable manner. Moreover, this concept fits into the latest trends in tissue engineering, which include biomaterials, bioactive factors and cells. Therefore, this review presents the latest literature reports on the properties of biomaterials enriched with platelet concentrates for applications in skin, nerve, cartilage and bone tissue engineering.

Two-Dimensional Radiographs and Cone-beam Computed Tomography Assessment of Concentrated Growth Factor and Platelet-Rich Fibrin Scaffolds in Regenerative Endodontic Treatment of Immature Incisors with Periapical Radiolucency: A Randomized Clinical Trial.

INTRODUCTION: The primary aim of this study was to compare the radiographic changes of immature incisors with periapical radiolucency after treatment with platelet-rich fibrin (PRF) and concentrated growth factor (CGF) platelet concentrate scaffolds as well as assessment of the clinical success rate over 12 months. The secondary aim was to monitor the radiographic changes in terms of reduction of periapical lesion diameter (PALD), root dentine thickness (RDT), root length (RL), and apical foramen width (AFW). The tertiary aim was to assess and pulp responses, after 12 months. METHODS: Fifty six children with seventy necrotic, single-rooted maxillary incisors with periapical radiolucency were treated with either CGF or PRF scaffolds (35 teeth per group). Two patients with 4 teeth (2 teeth in each group) failed to attain the follow-up recalls. Radiographic changes in terms of reduction of PALD, RDT, RL, and AFW were monitored using a 2-dimensional (2D) radiograph and cone-beam computed tomography (CBCT) scan. The clinical performance of teeth receiving both scaffolds was assessed after 6 and 12 months. Categorical and continuous data were analyzed using the chi-square test and the t test, respectively. The time and group effects on the means of different radiographic dimensions were tested using the general linear model. Bland-Altman plots were used to assess the level of agreement between the 2D radiographs and CBCT. The level of significance was defined at 0.05 and a 95% confidence interval. RESULTS: The means of PALD and RL showed significant enhancement in the CGF group compared to the PRF group (P < .05). While the difference between the 2 scaffolds in terms of RDT and AFW was not significant (P > .05). The findings of the 2D radiograph and CBCT were consistent. Clinically, both scaffold success rates were similar (93.9%) over the follow-up intervals. The influence of study independent variables had no significant effect on the success of the regenerative endodontic procedures outcome (P > .05). There was no significant difference in the positive pulp responses to the thermal and electric pulp tests after one year of treatment (P > .05). CONCLUSIONS: According to the short-term follow-up, PRF and CGF were successful in treating immature teeth with periapical radiolucency by regenerative endodontics. Both scaffold systems induced periapical healing and root lengthening with significant superiority of CGF.

An Update on Orthobiologics: Cautious Optimism.

Orthobiologics are rapidly growing in use given their potential to augment healing for multiple musculoskeletal conditions. Orthobiologics consist of a variety of treatments including platelet-rich plasma and stem cells that provide conceptual appeal in providing local delivery of growth factors and inflammation modulation. The lack of standardization in nomenclature and applications within the literature has led to a paucity of high-quality evidence to support their frequent use. The purpose of this review was to describe the current landscape of orthobiologics and the most recent evidence regarding their use.

Novel Applications of Concentrated Growth Factors in Facial Rejuvenation and Plastic Surgery.

Concentrated growth factor (CGF), which is a third-generation platelet concentrate product, exhibits good potential for repair and regeneration of soft and hard tissues, and has gradually attracted attention in the field of cosmetic plastic surgery. The purpose of this review is to summarize the application and research of CGF in the field of facial rejuvenation and plastic surgery. A comprehensive review of the literature about the applications of CGF in facial rejuvenation and plastic surgery was conducted in PubMed, Ovid MEDLINE, and Web of Science. According to the inclusion and exclusion criteria, a total of 22 articles were included in this review. In recent years, CGF has been applied in many aspects in the field of facial rejuvenation and plastic surgery, including skin photoaging, repairment of soft-tissue defects, rhinoplasty, hair loss, autologous fat transplantation, and scars. In addition, no significant adverse reactions have been reported so far. CGF is rich in high-concentration growth factors, which has great potential and application prospects in facial rejuvenation and plastic surgery. However, the applications of CGF still have some problems, such as the mechanism, time of decomposition, and long-term efficacy and safety, which are needed to be resolved in future.