Wound management, healing, and early prosthetic rehabilitation: Part 3 - A scoping review of chemical biomarkers

BACKGROUND:The timely provision of load-bearing prostheses significantly reduces healthcare costs and lowers post-amputation mortality risk. However, current methods for assessing residuum health remain subjective, underscoring the need for standardized, evidence-based approaches incorporating physical biomarkers to evaluate residual limb healing and determine readiness for prosthetic rehabilitation.OBJECTIVE(S):This review aimed to identify predictive, diagnostic, and indicative physical biomarkers of healing of the tissues and structures found in the residual limbs of adults with amputation.METHODOLOGY:A scoping review was conducted following Joanna Briggs Institute (JBI) and PRISMA-ScR guidance. Searches using “biomarkers”, “wound healing”, and “amputation” were performed on May 6, 2023, on Web of Science, Ovid MEDLINE, Ovid Embase, Scopus, Cochrane, PubMed, and CINAHL databases. Inclusion criteria were: 1) References to physical biomarkers and healing; 2) Residuum tissue healing; 3) Clear methodology with ethical approval; 4) Published from 2017 onwards. Articles were assessed for quality (QualSyst tool) and evidence level (JBI system), and categorized by study, wound, and model type. Physical biomarkers that were repeated not just within categories, but across more than one of the study categories were reported on.FINDINGS:The search strategy identified 3,306 sources, 157 of which met the inclusion criteria. Histology was the most frequently repeated physical biomarker used in 64 sources, offering crucial diagnostic insights into cellular healing processes. Additional repeated indicative and predictive physical biomarkers, including ankle-brachial index, oxygenation measures, perfusion, and blood pulse and pressure measurements, were reported in 25, 19, 13, and 12 sources, respectively, providing valuable data on tissue oxygenation and vascular health.CONCLUSION:Ultimately, adopting a multifaceted approach that integrates a diverse array of physical biomarkers (accounting for physiological factors and comorbidities known to influence healing) may substantially enhance our understanding of the healing process and inform the development of effective rehabilitation strategies for individuals undergoing amputation.

BACKGROUND:Following lower limb amputation, timely prosthetic fitting enhances mobility and quality of life. However, inconsistent definitions of surgical site healing complicate prosthesis readiness assessment and highlight the need for objective wound management measures.OBJECTIVE:This review aimed to compile definitions of healing and non-healing provided in the literature investigating biomarkers of healing of the tissues and structures found in the residual limbs of adults with amputation.METHODOLOGY:A scoping review was conducted following JBI and PRISMA-ScR guidance. Searches using “biomarkers,” “wound healing,” and “amputation” were performed on May 6, 2023, on Web of Science, Ovid MEDLINE, Ovid Embase, Scopus, Cochrane, PubMed, and CINAHL databases. Inclusion criteria were: 1) References to biomarkers and healing; 2) Residuum tissue healing; 3) Clear methodology with ethical approval; 4) Published from 2017 onwards. Articles were assessed for quality (QualSyst tool) and evidence level (JBI system).FINDINGS:Of 3,306 articles screened, 219 met the inclusion criteria and are reviewed in this article, with 77% rated strong quality. 43% of all included sources did not define healing, while the remainder used specific criteria including epithelialization (14%), wound size reduction (28%), gradings scales (3%), scarring (1%), absence of wound complications (2%), hydroxyproline levels (0.5%), no amputation (0.5%), or neovascularization (0.5%). 84% of included sources did not provide definitions of non-healing. Studies defining non-healing used criteria like wound complications (4%), the need for operative interventions (4%), or lack of wound size reduction (1%). For 10% of included sources, healing and non-healing definitions were considered not applicable given the research content. Total percentages exceed 100% for both healing and non-healing definitions because some sources used two definition classifications, such as epithelialization and wound size reduction. The findings indicate a lack of standardized definitions irrespective of study type.CONCLUSION:This review reveals significant gaps in current definitions of healing and non-healing, often based on superficial assessments that overlook deeper tissue healing and mechanical properties essential for prosthesis use. It emphasizes the need for comprehensive definitions incorporating biomarkers and psychosocial factors to improve wound management and post-amputation recovery.

Angiogenesis and vasculogenesis: Inducing the growth of new blood vessels and wound healing by stimulation of bone marrow–derived progenitor cell mobilization and homing

MMP-13 Plays a Role in Keratinocyte Migration, Angiogenesis, and Contraction in Mouse Skin Wound Healing

Contaminated wounds are common in all animals and human being; their treatments may complicated and need for prolong duration, therefore the current study aimed to investigate an alternative way to treat the contaminated wounds by using natural compounds that accelerate wounds healing; these study achieved on 30 local rabbits that exposed to surgical excision and contaminated by Staphylococcus aureus then divided into 5 groups in which 6 animals of each and treated for 14 days as the following: the first group treated with honey, second group treated with cod liver oil, third group treated with mixture of honey and cod liver oil, fourth group treated with fucidin while the fifth group contaminated with bacteria only. The results showed moderate (1.55 ± 0.11) wound contraction and healing in first group, while the second group showed (1.77 ± 0.10) was delayed in wound contraction and healing, the third group showed (1.0±0.13) which regarded the excellent and optimal wound contraction and healing, the fourth group showed (1.77 ± 0.12) which delayed wound healing and contraction, finally the fifth group showed(3.07 ± 0.11) in which no signs of wound contraction and healing. In conclusion, the using of mixture of natural compounds like honey and cod liver oil may accelerate wound contraction and healing and keep the wounds sterile.

Heparin-Binding Epidermal Growth Factor–Like Growth Factor as a Critical Mediator of Tissue Repair and Regeneration

Epidermal Development and Wound Healing in Matrix Metalloproteinase 13-Deficient Mice

Corneal wound healing is a complex process: its mechanisms and the underlying genetic control are not fully understood. It involves the integrated actions of multiple growth factors, cytokines and proteases produced by epithelial cells, stromal keratocytes, inflammatory cells and lacrimal gland cells. Following an epithelial insult, multiple cytokines are released triggering a cascade of events that leads to repair the epithelial defect and remodelling of the stroma to minimize the loss of transparency and function. In this review, we examine the literature surrounding the genomics of corneal wound healing with respect to the following topics: epithelial and stromal wound healing (including inhibition); corneal neovascularisation; the role of corneal nerves in wound healing; the endothelium; the role of aquaporins and aptamers. We also examine the effect of ectasia on corneal wound healing with regard to keratoconus and following corneal surgery. A better understanding of the cellular and molecular changes that occur during repair of corneal wounds will provide the opportunity to design treatments that selectively modulate key phases of the healing process resulting in scars that more closely resemble normal corneal architecture.

Tissue Transglutaminase Enhances Fibrin-Dependent Angiogenesis and Extracellular Matrix Formation by Altering Gene Expression during Wound Healing.

Angiogenesis is the formation of new blood vessels from the existing vasculature and is necessary for tumor growth. Syndecan-2 (S2) is highly expressed in the microvasculature of mouse gliomas. When S2 expression was down-regulated in mouse brain microvascular endothelial cells (MvEC), this inhibited cell motility and reduced the formation of capillary tube-like structures in vitro. Pro-angiogenic growth factors and enzymes up-regulated during glioma tumorigenesis stimulated shedding of the S2 ectodomain from endothelial cells in vitro. The effect of shed S2 on angiogenic processes was investigated by incorporating recombinant S2 ectodomain (S2ED) into in vitro angiogenesis assays. S2ED promoted membrane protrusion, migration, capillary tube formation, and cell-cell interactions. We therefore propose that S2 is necessary for angiogenesis of MvEC, proangiogenic factors expressed during glioma progression regulate S2 shedding, and shed S2 ectodomain may increase endothelial cell angiogenic processes.

Botulinum toxin is a neurotoxin that has been utilized to induce chemo-denervation of muscles. Cutaneous wounds represent a special situation in which the tensile forces applied by these muscles on wound edges might have deleterious effects on the healing process. The aim of this review was to investigate such an effect and to review other mechanisms this toxin might have on the healing process. We also reviewed the role of botulinum toxin in the management of hypertrophic scars and cleft lip repair.

To examine whether circulating levels of matrix metalloproteinase 9 (MMP-9) were associated with ultrasound-assessed intima-media thickness (IMT) and echolucent plaques in the carotid and femoral arteries. To examine preanalytical sources of variability in MMP-9 concentrations related to sampling procedures. Plasma and serum MMP-9 levels were compared with ultrasound assessed measures of femoral and carotid atherosclerosis, in a cross-sectional study of 61-year-old men (n = 473). Preanalytical sources of variability in MMP-9 levels were examined in 10 healthy subjects. Main outcome measures were circulating levels of MMP-9 in serum and plasma, IMT of the carotid and femoral arteries, and plaque status based on size and echolucency. Research unit at university hospital. Plasma concentrations of total and active MMP-9 were associated with femoral artery IMT independently of traditional cardiovascular risk factors, and were higher in subjects with moderate to large femoral plaques. Plasma MMP-9 concentration was higher in men with echolucent femoral plaques (P = 0.006) compared with subjects without femoral plaques. No similar associations were found for carotid plaques. MMP-9 concentrations were higher in serum than in plasma, and higher when sampling was performed with Vacutainer than with syringe. MMP-9 levels in serum were more strongly associated with peripheral neutrophil count compared with MMP-9 levels in plasma. Plasma MMP-9 levels were associated with atherosclerosis in the femoral artery, and total MMP-9 concentration was higher in men with echolucent femoral plaques. The choice of sample material and sampling method affect the measurements of circulating MMP-9 levels.

Collagenase-3 (MMP-13) Enhances Remodeling of Three-Dimensional Collagen and Promotes Survival of Human Skin Fibroblasts

Many studies have revealed the prominent roles of mast cells in wound healing, including inflammatory reactions, angiogenesis and extracellular matrix reabsorption. In the present study, we aimed to assess the probable therapeutic features of bromelain on wound contraction and mast cell degranulation in wound healing in experimental diabetic animals. Male rats were grouped as control, vehicle and experiment. Skin wounds were generated in all groups. Treatments were applied with distilled water and with bromelain (BR) intraperitoneally in the vehicle and experimental groups, respectively. Following skin wound generation, animals were euthanised on days 3, 5, 7 and 15. We gathered 16,800 microscopic images to count the mast cells and degranulation level (Image J software). The wound contraction index was assessed both microscopically (Image J software) and macroscopically (time-lapse photography). The meshwork evaluation method was used to assess wound healing. Time-lapse photography revealed that the BR significantly (p<0.05) accelerated wound contraction and healing. BR significantly (p<0.05) increased the total number of mast cells in all experimental groups on days 5 and 7. The count of grade III (degranulated) mast cells was reduced significantly (p<0.05) on days 5 and 7 in experimental groups compared to control and vehicle groups. In this study, the rate of wound healing was accelerated considerably following BR administration. In addition, this agent decreased the count of degranulated mast cells, leading to wound contraction and healing.

Wound healing is a fundamental process for survival. It makes an organism able to repair a damage and restore physiological condition. The whole process involves the coordinated interaction of many different cell populations and biochemical molecules, such as proteins, proteases, growth factors, and extracellular matrix (ECM) components. the possibility to carry out research in unloading conditions represents an unique tool to increase our knowledge on wound healing biomechanics and the role of gravity in the process. Moreover, in the perspective of longer-term space missions, with a growing number of astronauts involved, wound healing must be regarded as a serious problem, because the risk of injury due to traumatic events or unexpected emergency surgery will increase while medical evacuation times to Earth will become incompatible with the urgency of implementing assistance procedures. Therefore, it is crucial to understand the impact of microgravity (μg) on the mechanisms underlying wound healing. In the frame of these studies, we developed an in vivo model of wound healing based on leeches [Hirudo Medicinalis]. This invertebrate represents an interesting model, since the sequence of events occurring during the healing is similar as in vertebrates. Moreover, the leech is very resistant and, once nourished, can survive for some months without eating. For this reasons, it can be considered one the most suitable living beings to be used for experiments both in modeled and real μg, even during long-term space missions. The results of preliminary experiments about healing process are iullustrated and discussed