Normal Healing Process Research Articles

The Clinical Profile of Patients with Chronic Wounds at Dr. Soetomo General Hospital 2015-2020

Background: Wounds that have lasted a long time due to failure to continue the normal healing process can be called chronic wounds. Chronic wounds occur due to multiple factors. There are problems that are often found in chronic wounds, such as the presence of exudate, necrotic tissue, and bacteria. The incidence of chronic wounds is closely related to the high cost of treatment and impaired quality of life. Prompt wound management is needed to optimize wound healing. Purpose: To determine the profile of chronic wounds in patients treated by the Department of Plastic Surgery Dr. Soetomo General Hospital Surabaya from 2015 – 2020. Methods: The data were obtained from patients medical records through total sampling technique, which consist of age, gender, past medical history, clinical features, diagnosis, management, and outcome. Result: This study involved 53 patients, dominated by male patients (70%) aged 46-65 years old (34%). The patient’s history showed that most patients suffered from type 2 diabetes (22%). The problem that often occurs is the presence of exudate which is mostly diagnosed with pressure ulcers (40%). All patient get wound bed preparation and the patient's outcome was dominated by recovery (72%). Conclusion: There are several factors affecting wound healing and prompt wound management are important to improving the outcomes.

Biocompatible Macroion/Growth Factor Assemblies for Medical Applications.

Growth factors are a class of proteins that play a role in the proliferation (the increase in the number of cells resulting from cell division) and differentiation (when a cell undergoes changes in gene expression becoming a more specific type of cell) of cells. They can have both positive (accelerating the normal healing process) and negative effects (causing cancer) on disease progression and have potential applications in gene therapy and wound healing. However, their short half-life, low stability, and susceptibility to degradation by enzymes at body temperature make them easily degradable in vivo. To improve their effectiveness and stability, growth factors require carriers for delivery that protect them from heat, pH changes, and proteolysis. These carriers should also be able to deliver the growth factors to their intended destination. This review focuses on the current scientific literature concerning the physicochemical properties (such as biocompatibility, high affinity for binding growth factors, improved bioactivity and stability of the growth factors, protection from heat, pH changes or appropriate electric charge for growth factor attachment via electrostatic interactions) of macroions, growth factors, and macroion-growth factor assemblies, as well as their potential uses in medicine (e.g., diabetic wound healing, tissue regeneration, and cancer therapy). Specific attention is given to three types of growth factors: vascular endothelial growth factors, human fibroblast growth factors, and neurotrophins, as well as selected biocompatible synthetic macroions (obtained through standard polymerization techniques) and polysaccharides (natural macroions composed of repeating monomeric units of monosaccharides). Understanding the mechanisms by which growth factors bind to potential carriers could lead to more effective delivery methods for these proteins, which are of significant interest in the diagnosis and treatment of neurodegenerative and civilization diseases, as well as in the healing of chronic wounds.

Advances in Animal Models for Studying Bone Fracture Healing

Fracture is a common traumatic injury that is mostly caused by traffic accidents, falls, and falls from height. Fracture healing is a long-term and complex process, and the mode of repair and rate of healing are influenced by a variety of factors. The prevention, treatment, and rehabilitation of fractures are issues that urgently need to be addressed. The preparation of the right animal model can accurately simulate the occurrence of fractures, identify and observe normal and abnormal healing processes, study disease mechanisms, and optimize and develop specific treatment methods. We summarize the current status of fracture healing research, the characteristics of different animal models and the modeling methods for different fracture types, analyze their advantages and disadvantages, and provide a reference basis for basic experimental fracture modeling.

Commercial articulated collaborative in situ 3D bioprinter for skin wound healing.

In situ bioprinting is one of the most clinically relevant techniques in the emerging bioprinting technology because it could be performed directly on the human body in the operating room and it does not require bioreactors for post-printing tissue maturation. However, commercial in situ bioprinters are still not available on the market. In this study, we demonstrated the benefit of the originally developed first commercial articulated collaborative in situ bioprinter for the treatment of full-thickness wounds in rat and porcine models. We used an articulated and collaborative robotic arm from company KUKA and developed original printhead and correspondence software enabling in situ bioprinting on curve and moving surfaces. The results of in vitro and in vivo experiments show that in situ bioprinting of bioink induces a strong hydrogel adhesion and enables printing on curved surfaces of wet tissues with a high level of fidelity. The in situ bioprinter was convenient to use in the operating room. Additional in vitro experiments (in vitro collagen contraction assay and in vitro 3D angiogenesis assay) and histological analyses demonstrated that in situ bioprinting improves the quality of wound healing in rat and porcine skin wounds. The absence of interference with the normal process of wound healing and even certain improvement in the dynamics of this process strongly suggests that in situ bioprinting could be used as a novel therapeutic modality in wound healing.

Nanocatalytic Hydrogel with Rapid Photodisinfection and Robust Adhesion for Fortified Cutaneous Regeneration

Chronic inflammation caused by invasive bacterial infections severely interferes with the normal healing process of skin regeneration. Hypoxia of the infection microenvironment (IME) seriously affects the antibacterial effect of photodynamic therapy in phototherapy. To address this serious issue, a nanocatalytic hydrogel with an enhanced phototherapy effect consisting of a hydrogel polyvinyl alcohol (PVA) scaffold, MXene/CuS bio-heterojunction, and polydopamine (PDA) for photothermal antibacterial effects and promoting skin regeneration is designed. The MXene/CuS bio-heterojunction has a benign photothermal effect. Singlet oxygen (1O2) and hydroxyl radicals (·OH) were generated under near-infrared light, which made the hydrogel system have good antioxidant and antibacterial properties. The addition of PDA further improves the biocompatibility and endows the nanocatalytic hydrogel with adhesion. Additionally, in vivo assays display that the nanocatalytic hydrogel has good skin regeneration ability, including ability to kill bacteria, and promotes capillary angiogenesis and collagen deposition. This work proposes an approach for nanocatalyzed hydrogels with an activated IME response to treat wound infections by enhancing the phototherapeutic effects.

Microtomographic, histomorphometric, and molecular features show a normal alveolar bone healing process in iNOS-deficient mice along a compensatory upregulation of eNOS and nNOS isoforms.

Inducible nitric oxide synthase (iNOS) is one of the enzymes responsible for the synthesis of nitric oxide (NO), which is an important signaling molecule with effects on blood vessels, leukocytes, and bone cells. However, the role of iNOS in alveolar bone healing remains unclear. This study investigated the role of iNOS in alveolar bone healing after tooth extraction in mice. C57Bl/6 wild type (WT) and iNOS genetically deficient (iNOS-KO) mice were subjected to upper incision tooth extraction, and alveolar bone healing was evaluated by micro-computed tomography (μCT) and histological/histomorphometric, birefringence, and molecular methods. The expression of iNOS had very low control conditions, whereas a significant increase is observed in healing sites of WT mice, where iNOS mRNA levels peak at 7d time point, followed by a relative decrease at 14d and 21d. Regarding bone healing, both WT and iNOS-KO groups showed the usual phases characterized by the presence of clots, granulation tissue development along the inflammatory cell infiltration, angiogenesis, proliferation of fibroblasts and extracellular matrix synthesis, bone neoformation, and remodeling. The overall micro-computed tomography and histomorphometric and birefringence analyses showed similar bone healing readouts when WT and iNOS-KO strains are compared. Likewise, Real-Time PCR array analysis shows an overall similar gene expression pattern (including bone formation, bone resorption, and inflammatory and immunological markers) in healing sites of WT and iNOS-KO mice. Moreover, molecular analysis shows that nNOS and eNOS were significantly upregulated in the iNOS-KO group, suggesting that other NOS isoforms could compensate the absence of iNOS. The absence of iNOS does not result in a significant modulation of bone healing readouts in iNOS-KO mice. The upregulation of nNOS and eNOS may compensate iNOS absence, explaining the similar bone healing outcome in WT and iNOS-KO strains.

Influential factors of the success and/or failure of dental implants

Introduction: Dental prostheses are the most widely used artificial means to replace missing teeth in people, in order to restore the necessary harmony in the stomatognathic complex, both functional and aesthetic. Dental implants are pure titanium fixations that are placed in the maxillary or mandibular bone in order to replace the roots of missing teeth, currently they are one of the most innovative rehabilitative therapies in dentistry. Objective: Evaluate the factors that influence the success and/or failure of dental implants. Methodology: This research is framed within a systematic bibliographic review. Results: The factors that have the greatest influence and affect the immediate result are heavy smoking, implant placement under a torque of less than 15 Nm, overheating of the site, lack of primary stability at the time of implant placement, premature loading or microbiological contamination that alter the normal healing process of the soft tissues and prevent the intimate union between the bone and the implant from forming. Conclusion: Success and failure are dynamic conditions linked to time and require periodic evaluation. The main criteria to evaluate the quality of health of the dental implant are mobility and pain, the presence of any of them compromises the implant to a great extent. Non-osseointegration and peri-implantitis were the most frequent causes of failure in the initial phase of the treatment. Regarding the anatomical regions of the oral cavity, the failure rates were low and the survival and success rates were high.

Management of Chronic Non-Healing Ulcers by Topical Application of Platelet Rich Plasma (PRP)

Disturbance of the normal anatomic structure and functional integrity of the skin can be described as wound. Chronic or non-healing ulcers are defined as ulcers which are failed to heal in less than 3 weeks of duration .If normal healing process is interrupted ulcer can become chronic in nature due to lack of growth factors and cytokines which is results in delay of wound healing. Conventional treatment for chronic non-healing ulcers includes wound cleansing and necrotic tissue debridement. The use of patient’s own body cells for ulcer treatment relies upon the components present in the blood and platelet concentrate, which contains various cytokines and growth factors. Autologous PRP is a platelet suspension in plasma derived from whole blood that is increasingly being used in clinical practice for the treatment of chronic non healing ulcers. OBJECTIVE: To assess the efficacy of topical application of autologous platelet rich plasma in wound healings. METHODOLOGY: The study was conducted in the department of General Surgery, GREAT EASTERN MEDICAL SCIENCES during the period of February 2021 to February 2022 . Ten patients between 18-80 yrs ,of any sex, with chronic non-healing ulcers of different etiologies were treated with topical application of PRP. RESULTS : Ten patients each having ulcer of varying etiology were included .Treated with Topical administration of AUTOLOGOUS PRP solution over the ulcer. Among the included patients 6(60%) were males and 4 (40%) were females with a mean age of 62.5± 13.53 years. Out of 10 patients 4(40%) were in 61-80 years age group,2(20%)were in 41-60 years age group and 4(40%) patients was less than 40 years .The duration of the chronic non healing ulcers presented by the patients range from 9 to 24 weeks with a mean duration of 16weeks.After application of PRP solution ,the mean healing time was found to be almost 8.2 weeks±1.9weeks.After the application of PRP solution small islands of granulating tissue appeared over the wound and a significant reduction in ulcer size was observed as a sign of healing and improvement. CONCLUSION: In our study, the results showed that PRP is a safe and effective treatment modality for chronic non-healing ulcers. Delivering of growth factors to target site enhances the wound healing rates of chronic non healing ulcers.PRP seems to be efficient to treat chronic non healing ulcers which are non responsive to classical conservative treatments. Using PRP to treat chronic wounds/ulcers may not only enhance healing, but also prevent lower extremity amputations caused by nonhealing wounds.There by reducing over all hospital stay, inconvenience of constant medication and morbidity.

Advances of hydrogel combined with stem cells in promoting chronic wound healing.

Wounds can be divided into two categories, acute and chronic. Acute wounds heal through the normal wound healing process. However, chronic wounds take longer to heal, leading to inflammation, pain, serious complications, and an economic burden of treatment costs. In addition, diabetes and burns are common causes of chronic wounds that are difficult to treat. The rapid and thorough treatment of chronic wounds, including diabetes wounds and burns, represents a significant unmet medical need. Wound dressings play an essential role in chronic wound treatment. Various biomaterials for wound healing have been developed. Among these, hydrogels are widely used as wound care materials due to their good biocompatibility, moisturizing effect, adhesion, and ductility. Wound healing is a complex process influenced by multiple factors and regulatory mechanisms in which stem cells play an important role. With the deepening of stem cell and regenerative medicine research, chronic wound treatment using stem cells has become an important field in medical research. More importantly, the combination of stem cells and stem cell derivatives with hydrogel is an attractive research topic in hydrogel preparation that offers great potential in chronic wound treatment. This review will illustrate the development and application of advanced stem cell therapy-based hydrogels in chronic wound healing, especially in diabetic wounds and burns.

A Review on Chitosan and Cellulose Hydrogels for Wound Dressings.

Wound management remains a challenging issue around the world, although a lot of wound dressing materials have been produced for the treatment of chronic and acute wounds. Wound healing is a highly dynamic and complex regulatory process that involves four principal integrated phases, including hemostasis, inflammation, proliferation, and remodeling. Chronic non-healing wounds are wounds that heal significantly more slowly, fail to progress to all the phases of the normal wound healing process, and are usually stalled at the inflammatory phase. These wounds cause a lot of challenges to patients, such as severe emotional and physical stress and generate a considerable financial burden on patients and the general public healthcare system. It has been reported that about 1-2% of the global population suffers from chronic non-healing wounds during their lifetime in developed nations. Traditional wound dressings are dry, and therefore cannot provide moist environment for wound healing and do not possess antibacterial properties. Wound dressings that are currently used consist of bandages, films, foams, patches and hydrogels. Currently, hydrogels are gaining much attention as a result of their water-holding capacity, providing a moist wound-healing milieu. Chitosan is a biopolymer that has gained a lot of attention recently in the pharmaceutical industry due to its unique chemical and antibacterial nature. However, with its poor mechanical properties, chitosan is incorporated with other biopolymers, such as the cellulose of desirable biocompatibility, at the same time having the improved mechanical and physical properties of the hydrogels. This review focuses on the study of biopolymers, such as cellulose and chitosan hydrogels, for wound treatment.

Recent Advancement of Functional Hydrogels toward Diabetic Wound Management.

Wound healing is a dynamic, orchestrated process comprising partially overlapping phases of hemostasis, inflammation, proliferation, and remodeling. This programmed process, dysregulated in diabetic individuals, results in chronic diabetic wounds. The normal process of healing halts at the inflammatory stage, and this prolonged inflammatory phase is characteristic of diabetic wounds. There are a few U.S. Food & Drug Administration approved skin substitutes; dermal matrixes are commercially available to manage diabetic wounds. However, expensiveness and nonresponsiveness in a few instances are the major limitations of such modalities. To address the issues, several treatment strategies have been exploited to treat chronic wounds; among them hydrogel-based systems showed promise due to favorable properties such as excellent absorption capabilities, porous structure, tunable mechanical strength, and biocompatibility. In the past two decades, hydrogels have become one of the most acceptable systems in the field of wound dressing material, offering single functionality to multifunctionality. This review focuses on the advancement of functional hydrogels explored for diabetic wound management. The process of diabetic wound healing is discussed in the light of the normal healing process, and the role of macrophages in the process is explained. This review also discusses the different approaches to treat diabetic wounds using functional hydrogels, along with their future opportunities.

Burn-injured skin is marked by a prolonged local acute inflammatory response of innate immune cells and pro-inflammatory cytokines.

The systemic and local immune response in burn patients is often extreme and derailed. As excessive inflammation can damage healthy tissues and slow down the healing process, modulation of inflammatory responses could limit complications and improve recovery. Due to its complexity, more detailed information on the immune effects of thermal injury is needed to improve patient outcomes. We therefore characterized and quantified subsets of immune cells and mediators present in human burn wound tissue (eschar), sampled at various time points. This study shows that after burn injury, the number of immune cells were persistently increased, unlike the normal wound healing process. There was an immediate, strong increase in neutrophils and a moderate increase in monocytes/macrophages and lymphocytes, especially in the second and third week post burn. The percentage of classical (CD14highCD16-) monocytes/macrophages demonstrated a steady decrease over time, whereas the proportion of intermediate (CD14highCD16+) monocytes/macrophages slowly increased. The absolute numbers of T cells, NK cells and B cells increased up to week 3, while the fraction of γδ T cells was increased only in week 1. Secretome profiling revealed high levels of chemokines and an overall pro-inflammatory cytokine milieu in burn tissue. The local burn immune response shows similarities to the systemic immune reaction, but differs in neutrophil maturity and lymphocyte composition. Altogether, the neutrophil surges, high levels of pro-inflammatory cytokines and limited immunosuppression might be key factors that prolong the inflammation phase and delay the wound healing process in burns.

Patterns of Vertebral Bone Marrow Edema in the Normal Healing Process of Lumbar Interbody Fusion: Baseline Data for Diagnosis of Pathological Events.

Retrospective investigation using a prospectively collected database. To examine the appearance and characteristics of vertebral bone marrow edema (BME) in the normal healing of lumbar interbody fusion. Although BME in pathological spinal conditions has been well-documented, the patterns and characteristics of BME in the normal healing process of spinal fusion remains unexplored. We reviewed imaging from 225 patients with normal healing following posterior lumbar interbody fusion or transforaminal lumbar interbody fusion. BME was identified on magnetic resonance imaging at the third postoperative week and categorized with respect to its appearance, including assessment of area and extension within the relevant vertebrae. Three hundred eighty-nine of the 450 instrumented vertebrae (86.4%) displayed evidence BME. All instances of BME were associated with the area of contact with the endplate. The average extent of BME was 32.7±1.0%. BME within normal healing following interbody fusion could be categorized into four types: no edema (13.6%), anterior corner (36.6%), around-the-cage focal (48.0%), and diffuse (1.8%). Anterior corner BME was significantly associated with instances of single cage placement than in dual cages (42.6% vs. 24.7%, P =0.0002). Single cages had a significantly higher rate of BME than dual cages (92.0% vs. 75.3%, P <0.0001). The extent of BME was significantly greater in the single cage cohort (36.9% vs. 24.2% in dual cages, P <0.0001). This serves as the first study demonstrating the patterns of BME associated with normal healing following lumbar interbody fusion procedures. Anterior corner BME and around-the-cage focal BME were the most common patterns encountered, with diffuse BME a relatively rare pattern. These findings might contribute to the better differentiation of postoperative pathological events from normal healing following lumbar interbody fusion. 4.

Histopathological study to determine the effects of platelet rich fibrin membrane crafting on skin healing compared with MEBO scar ointment in rabbit

The present study aimed to compare between the use of platelet rich fibrin membrane (PRFM) and MEBO scar ointment for cutaneous wound healing as a model treatment. For this reason, forty two local breed rabbits have been divided into four groups, the first three groups were subjected to full thickness skin wound using biopsy punch instrument (diameter 8 mm) on the dorsal thoracic side. Rabbits in the first group leaved without treatment, while in the second group we planted the PRFM in biopsy site, the third group treated with MEBO scar ointment. Wound healing process was observed grossly and microscopically at day 3, 7, 10 and 12 post operation. All groups showed normal healing process with competitive advantage to PRFM and MEBO groups respectively compared with untreated group, PRFM was better than the MEBO group, the advantage characterized by less inflammatory reaction, fast reepitheliazation, granulation tissue formation, fibroplasias and angiogenesis.

Reactive Oxygen Species Suppressive Kraft Lignin-Gelatin Antioxidant Hydrogels for Chronic Wound Repair.

Chronic wound is difficult to repair because the normal wound healing mechanism is inhibited by the continuous inflammatory response. The delayed inflammatory responses generate high level of reactive oxygen species (ROS) at the wound sites, which leads to a longer inflammatory phase and induces a vicious cycle that interferes with the normal wound healing process. Therefore, ROS scavenging is an important factor for chronic wound healing. In this study, antioxidant hydrogel is developed by cross-linking kraft lignin, an antioxidant agent, and gelatin (Klig-Gel). Klig-Gel hydrogel is fabricated via ring opening reaction with epichlorohydrin as a cross-linker. High ROS scavenging activities are confirmed by various antioxidant evaluations, and in vitro natural antioxidant expression tests show reduction of oxidative stress. Mechanical properties of Klig-Gel hydrogel are tailorable by introducing different amount of kraft lignin to the hydrogel system. Biocompatibility is confirmed regardless of the kraft lignin content. Klig-Gel hydrogel is a promising ROS scavenging material that can be applied in various chronic wound healing applications.

Clinical diagnostics, differential diagnostics, pathogenesis and stage model of arthrofibrosis

Arthrofibrosis (AF) is one of the most frequent complications of injuries and surgical interventions on joints, particularly after total knee replacement and anterior cruciate ligament reconstruction. Even though all joints can be affected, most cases involve the knee joint. Patients feel apainful impairment of the range of motion caused by fibrotic tissue formation within and sometimes also outside the joint. The normal healing process is disturbed by mechanical and emotional stressors and severe pain. In 90% of the cases AF occurs even within the first few days after the injury or surgery, so that the quality standards cannot be achieved. Physiotherapy and rehabilitation often do not result in a substantial amelioration of symptoms, so that the activities of daily living (ADL) are severely limited. The clinical diagnostics, differential diagnostics and anovel pathogenesis and stage model of the primary AF with the treatment principles derived from this are presented in this article.

Water for wound cleansing.

Water for wound cleansing.

The outcome of sternum healing among diabetic patients undergoing open heart surgery: a literature review

Background: As part of the surgery, sternotomy is a common technique to expose the underlying organs, allowing surgeons to explore the targeted organ. Despite the benefits offered, it has several considerable complications; one of them is wound healing defect. The impairment of sternal wound healing after sternotomy could be superficial and/or deep. This condition is influenced by many factors, including diabetes mellitus, obesity, and other comorbidities. These anomalies will affect the normal healing process of the bone and other connective tissue, particularly after a major invasive event, such as in sternotomy. This study aimed to review the outcome of sternum healing among diabetics that underwent heart surgery with a sternotomy approach. Methods: Works of literature reviewed in this study were obtained from Pubmed and Google Scholar databases starting from 1992 until April 2022. The keywords used were ‘sternal wound healing’, ‘cardiac surgery’, and ‘diabetes mellitus’. An advanced search based on the exact phrases was conducted on Google Scholar. Gathered kinds of literature were then selected based on relevancy. Results: The majority of articles reviewed were observational, and most of them had CABG as a part of open heart surgery, followed by valvular and aortic surgeries and others. The incidence of impaired sternal healing and other complications (superficial and/or deep) was more commonly seen among patients with diabetes. Most studies also reported a significant correlation between DM and the incidence of impaired sternal healing, suggesting that DM was a significant predictor of it. Conclusion: Diabetes mellitus is a medical condition that must be taken into account among the candidates for open heart surgery, particularly if it is poorly controlled. The Hyperglycaemic state experienced by the patients will lead to multiorgan damage and immunological dysfunction that could affect the healing process of the sternum.

Review on Collagen as a wound healer.

In reaction to the tissue injury, normal wound healing process goes through inflammatory, proliferative, and remodeling stages. Impairments any one of these stages cause the wound to become chronic and non-healing, necessitating intervention to bring returning the process to its original state. Collagen, a fundamental has a role in the matrix extracellular an important function in wound healing regulation, whether in its native fibrillar form or in the wound as soluble components environment. Collagen has been used as an additional wound treatment to aid healing since it is involved in the control a combination of a few of these processes. The importance of collagen in various biological processes related to wound healing is discussed in this paper, additionally to a survey of the existing research in regards to the utilization of collagen-based wound care. There are several techniques to developing recommendations, but no gold standard has emerged so till now.&#x0D; &#x0D; &#x0D; &#x0D;

Antioxidant Silk Fibroin Composite Hydrogel for Rapid Healing of Diabetic Wound.

Wound healing is a complex process requiring multiple biological pathways and chemical responses to be activated and synchronized to recover tissue integrity. In normal physiological circumstances, the epidermal barrier restoration process through new tissue formation is highly efficient. However, increased production of reactive oxygen species (ROS), attack of pathogenic microorganisms, and high glucose level delay the normal healing process in diabetic patients. The successful treatment of diabetic wounds requires efficient strategies to control oxidative stress, promoting angiogenesis, re-epithelialization, and collagen deposition. In this study, a composite hydrogel for rapid wound healing in diabetic condition is developed by the amalgamation of hypolipidemic property of silk fibroin (SF), antioxidant property of melanin, and therapeutic effect of berberine. Studies have revealed that cross-linked mesoporous morphology of hydrogel matrix facilitates slow release of berberine to impart long-term therapeutic effects at wound site. The composite hydrogel formulation is biocompatible, stimulates effective migration of fibroblast cells, and control oxidative stress under in vitro conditions. The hydrogel served as scaffold for tissue re-epithelialization and promotes wound repair in diabetic type I Wistar rat model. This study demonstrates the ability of berberine- loaded SF-melanin composite hydrogel as a potential dressing formulation for wound healing in diabetic conditions.