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VOLUME 7, ISSUE 2 

 2024 
 

REVIEW ARTICLE 

Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-

healing definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

 

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https://doi.org/10.33137/cpoj.v7i2.43715


 

1 

Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

 

 

REVIEW ARTICLE 

 

WOUND MANAGEMENT, HEALING, AND EARLY PROSTHETIC REHABILITATION: PART 1 - 

A SCOPING REVIEW OF HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid H1, Johannesson A2, Buis A1*  

1 Department of Biomedical Engineering, Faculty of Engineering, University of Strathclyde, Glasgow, Scotland. 
2 Össur Clinics EMEA, Stockholm, Sweden.   

 
  
 

 

 

 

  

 

 

 

 

 

 

 

 

 

 

 

 

INTRODUCTION   

 

1: OVERALL RATIONALE, AIMS, AND OBJECTIVES 

The term “wound” broadly refers to damage to any biological 

tissue,1 encompassing damage from amputation surgery to 

deep tissue  injuries  caused  by  loading  during  lower limb  

 

 

 

 

prosthetic use. The healthy, or normal, wound healing 

process is marked by four interlinked physiologic phases 

(Table 1): I) hemostasis, II) inflammation, III) proliferation, 

and IV) tissue remodeling (or resolution).2-4 This complex 

process demands a high degree of cellular coordination, 

including several avenues through which impairments can 

occur. Consequently, wound healing can be stalled (also 

referred to as non-healing, impaired, or chronic) not by one 

isolated factor, but by several smaller contributing issues.5 

For example, common post-amputation surgical site healing 

complications include infection, pain, hematomas, tissue 

necrosis, poor residual limb formation, recurrent ulceration, 

wound dehiscence, and stitch abscesses.6,7 Persistent 

complications, in other words, poor healing, can necessitate 

 
OPEN  ACCESS 

ABSTRACT 

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. 

 

 

 

ARTICLE INFO 

Received: July 5, 2024 

Accepted: October 25, 2024 

Published: November 15, 2024 
 

CITATION 

Williams-Reid H, Johannesson A, 

Buis A. Wound management, 

healing, and early prosthetic 

rehabilitation: Part 1 - A scoping 

review of healing and non-healing 

definitions. Canadian Prosthetics 

& Orthotics Journal. 2024; 

Volume 7, Issue 2, No.1. 

https://doi.org/10.33137/cpoj.v7i2

.43715 

KEYWORDS 

Amputation, Scoping Review, 

Wound Healing, Wound Non-

Healing, Surgical Site Healing, 

Biomarkers, Markers of Healing, 

Residuum Healing, Residual Limb 

Healing, Wound Management, 

Impaired Healing. 

Please refer to the end of the 

article for a list of Abbreviations 

& Acronyms. 

 

* CORRESPONDING AUTHOR: 

Professor Arjan Buis, PhD 

Department of Biomedical Engineering, Faculty of Engineering, University 
of Strathclyde, Glasgow, Scotland. 

E-Mail: arjan.buis@strath.ac.uk 

ORCID ID: https://orcid.org/0000-0003-3947-293X 

 

Journal Homepage: https://jps.library.utoronto.ca/index.php/cpoj/index 

Volume 7, Issue 2, Article No.1. 2024 

 

 

https://doi.org/10.33137/cpoj.v7i2.43715
https://doi.org/10.33137/cpoj.v7i2.43715
https://doi.org/10.33137/cpoj.v7i2.43715
mailto:arjan.buis@strath.ac.uk
https://orcid.org/0000-0003-3947-293X
https://jps.library.utoronto.ca/index.php/cpoj/index


 

2 

Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

revision surgeries or even re-amputation at more proximal 

levels.6 Despite the intricacies of the wound healing 

process, the current assessment of healing relies mainly on 

surface level clinician examinations and wound 

classification systems. For instance, the East London NHS 

(National Health Service) Trust's clinical guidelines 

recommend using a disposable measuring tape to monitor 

wound healing by assessing wound length and width.8 Such 

subjective methods introduce biases and fail to account for 

underlying issues. Deep tissue injuries (DTIs), for example, 

develop subcutaneously and only become visible in later 

stages, manifesting as bruised purple localized areas of 

intact skin9 that can evolve into large deep wounds.10 This 

introduces the need for more objective measures to assess 

healing both at the surface level and below the cutaneous 

layer. 

This necessity for more objective measures is particularly 

pertinent in managing residual limbs following lower limb 

amputation. Following their surgery, depending on the 

healing process, individuals who have undergone lower 

limb amputation will typically receive a customized 

prosthetic limb within a window of 3 to 20 weeks post-

surgery.11,12 These prosthetic interventions are bespoke 

devices aimed to replicate the missing limb function, 

enhancing the user’s mobility, ambulation, and ability to 

perform daily tasks. Consequently, they significantly 

improve physical health, cardiovascular well-being, mental 

health, quality of life, and overall independence.12,13 

Notably, Singh and Prasad14 reported that the absence of a 

prosthetic limb fitting is an independent predictor of mortality 

within three years of a major lower limb amputation, defined 

as the loss of the limb at or proximal to the ankle joint.15  

However, assessing residuum healing and thus readiness 

for a prosthesis after amputation, like wound healing, 

remains ambiguous, involving clinician opinion, and surface 

level wound examination. In a narrative review of 

determinants of healing and readiness for prosthetic fitting 

after transtibial amputation, Day et al.16 concluded that 

clinical judgement is most subjective when assessing the 

degree of healing. Online resources for individuals with 

amputation similarly note that readiness for prosthetic fitting 

is dependent on factors such as healing, pain management, 

oedema, and residual limb volume,17 yet specific indicators 

for these factors remain undefined. Even healthcare bodies 

like the NHS provide no clear guidelines on assessing 

readiness, relying instead on clinicians’ experience and 

judgement, which can vary widely. For instance, Turner et 

al.18 in their thematic analysis of issues faced by prosthetists 

and physiotherapists during lower limb prosthetic 

rehabilitation, noted that clinicians lack a standardized 

approach to prosthetic rehabilitation. To illustrate, some 

prosthetists prefer removing a prosthesis to promote wound 

healing, whereas others believe continuing to wear it is 

more beneficial by encouraging blood flow.18 Furthermore, 

recent studies suggest that a limb does not need to be fully 

healed to begin prosthetic rehabilitation,16 but clear 

guidelines for when an open surgical site is appropriate for 

prosthetic use are still lacking. One prosthetist 

emphasized18 that “we have to go at the rate of the body,” 

noting that limbs heal and mature at different rates, further 

underscoring the variability in both clinical practice and 

patient recovery trajectories. Moreover, individuals awaiting 

amputation often present with multiple comorbidities that 

complicate their healing process. One of the most common 

causes of amputation is complications arising from 

diabetes,19 yet hyperglycemia can lead to vascular 

stiffening, microvascular dysfunction, reduced tissue 

oxygenation, and, consequently, impaired wound healing.20  

The complexity of defining readiness for prosthetic 

rehabilitation, coupled with the lack of standardized clinical 

practices, suggests the need for more objective measures, 

such as biomarkers, to assess healing and reduce the risk 

of complications like revision surgeries or re-amputations. A 

biomarker is defined by the U.S. FDA (Food & Drug 

Administration) as a “defined characteristic that is measured 

as an indicator of normal biological processes, a pathogenic 

process or a response to an exposure or intervention”.21 

Additional scholarly works have extended the FDA's 

definition by emphasizing the requirement for objectivity22 

and the importance of accurate and reproducible 

measurements.23 However, to the authors’ knowledge, 

research into the use of biomarkers for monitoring healing 

and facilitating early prosthetic rehabilitation post-

amputation remains limited. Studies that do exist, such as 

those focusing on changes in tissue composition during 

prosthetic use,24 typically examine mature residual limbs, 

whereas early-stage residual limbs face greater risks of 

complications like ulceration and volume changes, which 

exacerbate poor socket fit.25 Research into these early 

stages is crucial for ensuring successful prosthetic 

rehabilitation and preventing further surgical interventions. 

Table 1*: Characteristics and time frames of the four primary interlinked phases of wound healing. 

Phase Characterization Time Frame 

I (Hemostasis) 
Directly after injury, there is an outpouring of lymphatic fluid and blood. This involves platelet aggregation 
(blood clotting) and blood vessel vasoconstriction to prevent further bleeding.  

Seconds to Hours 

II (Inflammation) 
Cellular debris and bacteria are removed. Vascular permeability is increased to promote the diffusion of 
necessary molecules to the wound site. Cellular migration is similarly increased, as is chemotaxis. The aim 
is to limit further damage.   

Hours to Days 

III (Proliferation) 
Formation of granulation tissue (the contractile organ that fills wounds that heal by second intention), 
reepithelization (epidermis regeneration), and neovascularization.  

Days to Weeks 

IV (Remodeling) 
Defined by vascular maturation and regression, and collagen remodeling. The wound reaches its maximum 
strength and its ultimate endpoint; in cutaneous tissue, this is marked by a collagenous scar.   

Weeks to Months 

*Adapted from References 2-4.  

 

https://doi.org/10.33137/cpoj.v7i2.43715


 

3 

Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

This raises the following research question: What 

biomarkers (physical, chemical, or other) are predictive, 

diagnostic, and/or indicative of healing of the tissues and 

structures found in the residual limbs of adults with 

amputation? 

In summary, as noted by Patel et al.26 advances in 

genomics, proteomics, and molecular pathology have led to 

the identification of several candidate biomarkers with 

potential clinical value. However, progress in this area 

remains slow, and there is little consensus in the literature 

regarding the most appropriate biomarkers for assessing 

healing.22 Furthermore, to the authors’ knowledge, no 

comprehensive review exists that synthesizes biomarkers 

specifically related to healing after amputation.  

The most recent study examining readiness for prosthetic 

rehabilitation following transtibial amputation concluded that 

the only objective healing assessment used in the included 

studies was transcutaneous oxygen perfusion, a physical 

biomarker.16 The review emphasized that objective 

methodologies like this could quantify healing, reduce 

subjectivity, and promote comparative research on different 

enhanced recovery after surgery protocols and their effects 

on post-amputation healing.16  

Existing reviews are typically narrative in nature, discussing 

general wound healing biomarkers without a systematic 

approach, further highlighting the need for a more 

structured review of biomarkers specific to healing in the 

context of amputation and primary wound healing post-

surgery. To address this gap a scoping review was 

developed and implemented to compile the breadth of 

available wound healing biomarker evidence and answer 

the research question. The aim of the review was therefore 

to identify predictive, diagnostic, and/or indicative 

biomarkers (physical, chemical, or other) of healing of the 

tissues and structures found in the residual limbs of adults 

with amputation. To meet this aim and answer the research 

question, the following objectives were compiled: 

1) Collate and synthesize the reported definitions of healing 

and non-healing in the literature investigating healing of the 

tissues and structures found in the residual limbs of adults 

with amputation. 

2) Identify and collate physical biomarkers predictive, 

diagnostic, and/or indicative of healing repeated in sources 

investigating healing of the tissues and structures found in 

the residual limbs of adults with amputation.  

3) Identify and collate chemical biomarkers predictive, 

diagnostic, and/or indicative of healing repeated in sources 

investigating healing of the tissues and structures found in 

the residual limbs of adults with amputation. 

4) Assess the quality and levels of evidence of sources 

investigating healing of the tissues and structures found in 

the residual limbs of adults with amputation.   

The term “physical” refers to biomarkers such as pH, 

temperature of the wound, or collagen quantity revealed 

through histochemical staining,27 whereas the term 

“chemical” refers to markers found in wound tissue, fluid, 

serum/blood, sebum, saliva, or sweat such as cytokines or 

matrix metalloproteinases (MMPs).  

2: PART 1 - RATIONALE, AIMS, AND OBJECTIVES 

This article (Part 1) addresses Objectives 1 and 4 and is the 

first in a series of three articles, each of which explores 

Objectives 1 to 3 in turn. Before objective measures of 

healing can be developed, it is essential to first clarify the 

current definitions of healing. The timing of prosthetic 

rehabilitation, for instance, is contingent upon how healing, 

and consequently readiness for prosthetic fitting, is defined. 

Likewise, effective wound management hinges on the 

criteria used to distinguish between a healed and an 

unhealed wound. However, the literature reveals a lack of 

consensus on the definitions of healing and non-healing 

wounds.28 

While complete healing is often characterized by the 

“complete epithelialization” of the wound,29-31 this 

description neglects the underlying tissue layers. Where 

definitions of healing fall short, defining non-healing may be 

a useful alternative. Yet, definitions of impaired healing 

(commonly referred to as non-healing, chronic wound 

healing, or delayed healing) also exhibit significant 

variability. For instance, Furuyama et al.32 define non-

healing ulcers as wounds resulting in “major amputation or 

death before achieving ulcer healing”, whereas another 

source considers a chronic wound to be one that “has not 

shown a 20-40% reduction in wound area after 2-4 weeks 

of optimal treatment”.33 Relying solely on temporal criteria 

to distinguish healing from non-healing can be problematic. 

For example, research has shown that while older adults 

may experience delayed healing, the ultimate outcome 

remains comparable to that of younger individuals.34 

Additionally, Day et al.16 found that in their review of 

determinants of healing and readiness for prosthetic fitting, 

healing was undefined in 13 of the 15 studies reviewed. 

They also noted that the absence of standard healing 

definitions, the heterogeneity of measurable endpoints, and 

the inconsistent reporting of healing across studies 

significantly hinder the extrapolation of findings.  

In light of these challenges, the following article aims to 

answer the research question: How are healing and non-

healing defined in the literature investigating biomarkers of 

healing of the tissues and structures found in the residual 

limbs of adults with amputation?  

The aim of this article is therefore to compile definitions of 

healing and non-healing that are provided in the literature 

investigating biomarkers of healing of tissues and structures 

found in the residual limbs of adults with amputation. 

https://doi.org/10.33137/cpoj.v7i2.43715


 

4 

Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

METHODOLOGY 

Given the novelty of the research question and the variable 

sources available on biomarkers, a scoping review was 

deemed the most appropriate method to meet the aims and 

objectives and answer the research question. The scoping 

review was based upon the Joanna Briggs Institute (JBI) 

methodology for scoping reviews35-38 and implemented 

following the Preferred Reporting Items for Systematic 

Reviews extension for Scoping Reviews (PRISMA-ScR) 

checklist and guidance.39,40 All results were tracked and 

recorded on Excel Version Number 2303 (Microsoft, 

Washington, USA) run on Windows 11 Version 22H2 

(Microsoft, Washington, USA). A scoping review is 

iterative,41 with several steps requiring piloting; thus, the 

methodology presented in the following sections represents 

the final iterations of these processes. 

1: INCLUSION CRITERIA 

The following sections detail and rationalize the inclusion 

criteria of the scoping review culminating in the generation 

of an inclusion tool (Table 2) used in the first and second 

rounds of screening. 

1.1: Participants 

To minimize the ethical considerations associated with 

studies involving children, given that healing in adults and 

children reportedly differs,42,43 only sources involving adult 

participants were included. In line with common practice in 

literature44 and UK law (the setting in which this research 

takes place), an adult is defined as an individual older than 

or equal to 18 years of age.45  

A further inclusionary criterion was that participants must be 

experiencing some form of clearly described wound in 

tissues and structures comparable to that of an amputation 

residuum (Table 3). For example, the study by Giesen et 

al.46 meets the inclusion criteria despite focusing on risk 

factors, such as C-reactive protein (CRP) biomarker levels, 

for surgical site infections (SSI) following appendectomy. 

SSI is relevant as it can result in a non-healing wound.47 

Although the infection in this case occurs at the appendix, it 

affects the surrounding skin and soft tissue. This tissue is 

biologically comparable to that found at an amputation 

surgical site, thereby making the findings applicable to the 

study’s context. 

1.2: Types of Sources 

All the source types expressed in the following list were 

considered for inclusion to ensure the breadth of research 

was captured: 

• Quantitative studies 

This includes any study design, including retrospective/ 

prospective cohort studies, randomized controlled trials 

(RCTs),48 and in vitro, in silico, or rat/mouse studies. 

Note that rats/mice are considered sufficiently 

genetically similar to humans and are often used in 

biological research49 and will thus be included in this 

review. Where human participants were involved, the 

articles must clearly state whether ethical approval and 

informed consent were provided to meet the eligibility 

criteria.  

• Qualitative studies 

• Mixed studies 

• Case studies 

• Conference proceedings 

• Dissertations and theses 

• Text and opinion articles 

• Letters to editors 

These may be of value given their purpose to act as a 

form of post-publication peer review and the platform 

they give researchers to share experiences with fellow 

readers.50 

• Guidelines issued by national and international wound and 

tissue viability associations 

Examples of this include the National Institute for Health 

and Care Excellence (NICE) guidance on “Prontosan for 

treating acute and chronic wounds”51 and the NHS 

“Wound Management Clinical Practice Guidelines”.8 

However, all sources included were required to be 

reproducible, necessitating that their methodologies be 

clearly outlined. As a result, sources such as letters to 

 

Table 2: Inclusion criteria tool applied to each source during the first (title and abstracts) and second (full text) screening processes. To pass 

screening one, sources required all ‘Yes’ or ‘Maybe’ answers. To pass screening two on the other hand, and be included in data extraction, 

sources needed ‘Yes’ responses to all inclusion criteria. 

Evidence Source Details and Characteristics 

Citation  

Primary Author (Year)  

Title  

Abstract  

Inclusion Criteria for Screening One Yes No Maybe 

1 Does it reference biomarkers of wound healing (progression/monitoring/prediction)?    

2 Does it refer to healing of tissues found in the residuum?    

3 Is it published during or after 2017?    

Inclusion Criteria for Screening Two Yes No 

1 Does it reference biomarkers of wound healing (progression/monitoring/prediction)?   

2 Does it refer to healing of tissues found in the residuum?   

3 Does the source involve human/rat/mice participants? If it involves human participants, are they over 18 years old?   

4 Is it published during or after 2017?   

5 Is the methodology clear/repeatable?   

6 Does the study have clear ethical approval?   

 

 

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Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

editors and conference proceedings generally did not meet 

the inclusion criteria (Figure 1). Review articles were 

considered secondary sources and excluded.  

Table 3: For clarity this table provides examples of tissues/ 

structures found in the amputation residuum and those not. 

Examples of Tissues/Structures Found in the Residuum 

Skin, muscle and tendons, ligaments, bone, vasculature, and the 
peripheral nervous system. 

Examples of Tissue/Structures Not Found in the Residuum 

The central nervous system, and organs like the heart, brain, stomach, 
intestines, etc. 

 

The extensive number of sources generated during the 

initial searches prompted a reassessment of the inclusion 

criteria. Additionally, the rapid advancements in wound 

healing biomarkers48 underscored the necessity for more 

recent data. A recent scoping review examined prognostic 

factors (biomarkers) associated with ulcer healing, a 

common diabetic complication that can precede 

amputation,52 specifically focusing on sources published 

before 2017.53 In light of this context, it was decided to 

include only sources published in or after 2017, thereby 

ensuring the relevance and timeliness of the reviewed 

literature.  

1.3: Concept (Interventions and Outcomes) 

Sources were required to explore biomarker(s) in 

conjunction with wound healing. A relationship between the 

biomarker (independent variable) and non-healing/healing 

(dependent variable) was required for quantitative, 

observational, and mixed studies. A result was considered 

conclusive when a statistical significance of p < 0.05 was 

achieved. However, measuring biomarkers can be a 

continuous or categorical variable, thus any sources using 

cut-off or dichotomizing/categorizing approaches were also 

included.48 

1.4: Context  

Sources of any context (e.g., home, hospital, community, or 

academic institutions) and from any discipline (e.g., 

healthcare professionals or engineers) were considered to 

capture as much research as possible. Similarly, provided 

they were in the English language due to the linguistic 

limitations of the primary reviewer, sources from any 

geographical setting were considered to minimize high-

income-country (HIC) and Western publication bias.54,55 

2: SEARCH METHODS FOR IDENTIFICATION OF 

SOURCES 

According to the three-step search strategy recommended 

by JBI, an initial search was carried out on Medline via Ovid 

and PubMed to locate relevant sources and determine 

whether or not they could contribute to increasing search 

terms and keywords.56 Following the generation of an 

exhaustive list of terms based on the research question, and 

search strategy piloting, the search terms detailed in  

Table 4 were decided upon. 

Table 4: Search terms and indexing used to generate all sources 

screened in the final scoping review. Note the proximity search 

“adj5” index applies only to Ovid databases and differs according 

to the database. 

Biomarker 

Biomarker* 

Marker* 

Indicator* 

Factor* 

Amputation 

Amputee* 

Amputation* 

Residuum* 

Stump* 

Limb Loss 

Wound Healing 

Wound adj5 Sensing 

Wound adj5 Sensor 

Heal/Heals/Healed/Healing 

Monitor/Monitoring 

Sensor/Sense/Sensing 

Wound adj5 Healing 

Wound adj5 Monitoring 

Wound adj5 Monitor  
 

In a scoping review of scoping reviews, Pham et al.57 

concluded that the most frequent limitation was the 

possibility of missing relevant sources, which can be 

attributed to database selection. To counteract this, a 

significant number of databases mentioned in previous 

scoping reviews of a similar nature48,58,59 were searched: 

• Web of Science 

• MELDINE (hosted on the Ovid platform) 

• Embase (hosted on the Ovid platform) 

• Scopus  

• Cochrane 

• PubMed  

• CINAHL 

All search results were exported and stored in EndNote 20 

(Version 20.2.1, Clarivate, 2021) and duplicates were 

removed.  

3: DATA EXTRACTION  

Articles that passed both screening steps and met the 

eligibility criteria were then subjected to data extraction. 

Data (including study type, definitions of healing and non-

healing, wound details, sample type, sample size, and 

levels and quality of evidence) was extracted in accordance 

with the data extraction tool (APPENDIX A). Despite the 

debate surrounding the use of quality assessment in 

scoping reviews,41,60 it was decided to systematically 

demonstrate that the quality of evidence collated was 

acceptable to enhance the validation of the results of this 

review. The QualSyst tool (APPENDIX B) proposed by the 

Alberta Heritage Foundation61 was decided upon given that 

it outputs a number providing a quantitative and 

reproducible means of identifying quality that other critical 

appraisal tools do not.62 The outputted score allows a 

source to be categorized as limited, adequate, good, or 

strong quality. Similarly, evidence levels were assessed 

using the JBI levels of evidence (APPENDIX C).  

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Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

High numbers of poor-quality and low-level evidence could 

be considered indicative of a need for improvements in 

biomarker research methods.  

4: DATA ANALYSIS AND PRESENTATION 

The nature of a scoping review does not lend itself to a 

meta-analysis, thus it is recommended that it should instead 

focus on basic descriptive analysis such as frequency 

counts of concepts. Peter et al.35 further state that in some 

cases basic coding in a review proves useful particularly 

when identifying or clarifying definitions. Since the objective 

of this review requires the synthesis of wound healing 

definitions, coding is justified. To explore relationships 

between study types and definitions of healing and non-

healings, results are subdivided into study types with 

frequency counts of definitions within these study types 

identified.  

Extracted data is expressed in two primary formats. The first 

is a summary of the search results and selection process,35 

including a PRISMA diagram. The second is the 

presentation of the data extracted from the included 

sources, in such a format that the research question is 

answered. Results are descriptively presented in 

paragraphs that align with the review's objectives and are 

diagrammatically mapped. Charts allow frequency counts to 

be graphically visualized. It is well-known that data 

visualizations enhance understanding.63 All charted data 

(including source references) are openly available in the 

review’s dataset64 stored on the University of Strathclyde 

KnowledgeBase.  

RESULTS 

1: OVERALL RESULTS 

1.1: Search Strategy Results and Included Articles 

Of the 7,041 sources generated from the search strategy 

(Table 5), 3,735 were duplicates, so 3,306 titles and 

abstracts were screened (Figure 1). 2,659 sources were 

excluded, leaving 647 for full-text screening. After 

exclusion, 219 articles remained and were subjected to data 

extraction. Primary reasons for exclusion included review 

articles, unclear methodologies, no ethical approval, 

inaccessible texts, language constraints, irrelevant wound 

healing, and a lack of focus or discussion on biomarkers. 

1.2: Quality and Levels of Evidence 

All included evidence was quantitative with 77% of all 

studies29,31,32,46,65-229 demonstrating strong quality, and 0 

studies graded with limited quality (Table 6). Evidence 

levels, on the other hand, varied more; for Prognosis 35 

studies were graded level 1.b (the second highest level of 

evidence), and 4 (Table 7) were graded 5.c (the lowest level 

of evidence), whereas for Effectiveness, 1 and 12 studies 

were graded 1.b and 1.c, respectively. However, 98 studies 

were graded 5.c (Table 7).  

Study types additionally meant that no studies were graded 

for Meaning or Economic Evaluation levels of evidence. For 

levels of evidence, it is important to note that the total 

frequency counts add up to greater than 219 (the number of 

included articles) given that several studies were graded in 

more than one evidence level category; for example, often 

when graded for Prognosis, they were additionally graded 

for Effectiveness. Interestingly, 153 (70% of 219) were 

graded for Effectiveness, yet only 14 (6% of 219) met the 

criteria to be graded for Diagnosis (Table 7). 

1.3: Study Types and Settings 

The most common study type was bench research, with 99 

studies of this kind and only 6 case-controlled studies (Table 

8). The most common setting research took place in was a 

university environment (190 studies), whereas only 1 study 

occurred in a governmental organization setting (Table 9). 

66 and 35 studies were conducted in medical centers and 

research centers, respectively (Table 9). Note that the 

counts of settings and countries exceed 219 because 76 

(35%) of the articles took place in more than one setting, 

and 26 (12%) of articles took place in more than one 

country. All included articles came from 40 countries, with 

56 studies affiliated with China alone (Table 10). Whereas, 

only 7 and 3 articles were based in the UK and Ireland, 

respectively. 

Table 5: Breakdown of the search strategy results for each searched database. 

Database Search Date 
Number of 

Results 
Limited to Abstracts, Titles, Keywords 

(specifics of the applied limit) 
Limited to 2017 

and after 

Web of Science 06/05/2023 4,924 2,087 (abstract limit) 931 

Ovid Medline 06/05/2023 2,942 2,852 (abstract limit) 1,086 

Ovid Embase 06/05/2023 4,050 3,934 (abstract limit) 1,818 

Scopus 06/05/2023 4,534 4,534 (title, abstract, keyword limit) 1,828 

PubMed 06/05/2023 3,833 2,199 (title, abstract limit) 916 

CINAHL 06/05/2023 1,014 505 (abstract limit) 245 

Cochrane 

Cochrane Reviews 06/05/2023 202 16 (title, abstract, keyword limit) 8 

Cochrane Protocols 06/05/2023 30 0 (title, abstract, keyword limit) 0 

Cochrane Trials 06/05/2023 318 312 (title, abstract, keyword limit) 209 

    Total References 7,041 

    Duplicates Removed 3,735 

    Total References to Screen 3,306 

 

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7 

Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Identification of Studies via Databases and Registers 

Records identified from 7 databases (n = 7,041) 

Records screened (n = 3,306) 

Reports sought for retrieval (n = 647) 

Reports assessed for eligibility (n = 646) 

Studies included in review (n = 219): 

• Part 1 – Review of Healing and Non-Healing Definitions (n = 219) 
• Part 2 – Review of Physical Biomarkers (n = 157) 
• Part 3 – Review of Chemical Biomarkers (n = 203) 

Records excluded (n = 2,659) 

Reports not retrieved (n = 1) 

Reports excluded (n = 427): 

• Full methodology and results not sufficiently clear: 
• Clinical trial registry (n = 26) 
• Conference/Meeting abstract (n = 101) 
• Letter to editor (n = 2) 
• Article commentary or supplement (n = 2) 
• Study proposal (n = 2) 
• Short report (n = 1) 

• Review articles (n = 133) 
• Does not discuss biomarkers (n = 50) 
• Does not discuss wound healing (n = 28) 
• Does not correlate biomarkers with wound healing (n = 19) 
• Wound healing is discussed in tissue not relevant to the residuum (n = 17) 
• Duplicates (n = 6) 
• Dataset only (n = 3) 
• DOI not recognized (n = 3) 
• No ethical approval stated (n = 2) 
• Patent only (n = 2)  
• Study published before 2017 (n = 2) 
• Includes participants below 18 years old (n = 1) 

Id
e
n
ti
fi
c
a
ti
o

n
 

S
c
re

e
n
in

g
 

In
c
lu

d
e
d
 

Duplicates removed (n = 3,735) 

Figure 1: PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram of the scoping review screening process. 

 

Table 6: Ranking criteria for scores generated using the QualSyst quality assessment tool61 and numbers of included sources that obtained these 

rankings (NA = Not Applicable). 

Quality Threshold Scores 
Number (%) of 

Included 
Sources 

References of Included Sources Percentage (%) of Maximum Possible 
Score 

Quality 

< 50% Limited 0 (0%) NA 

≥ 50% and < 70% Adequate 9 (4%) 231, 234, 235, 241, 253, 263, 270, 272, 274 

≥ 70% and < 80% Good 41 (19%) 
230, 232, 233, 236-240, 242-252, 254-262, 264-269, 271, 

273, 275-279 

≥ 80% Strong 169 (77%) 29, 31, 32, 46, 65-229  

 

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8 

Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

2: DEFINITIONS 

2.1: Healing Definitions 

As depicted in Figure 2, 43% (n = 95) of included sources 

(all study types) provided no definition of healing. When 

definitions were provided, healing was most explained by 

complete epithelization/healing and change in wound 

area/size, utilised in 14% (n = 30) and 28% (n = 61) of 

sources respectively. Changes in wound area were most 

often used in bench research studies (92% of included 

sources using this definition) and were commonly presented 

as a wound healing rate defined as follows (Equation (1)): 

Wound Healing Rate (%)  =  
S0-St

S0

× 100% 

Where S0 is the original wound area, and St refers to the 

wound area at any given time after injury. Interestingly only 

one source242 incorporated biomarkers in their definition of 

healing, using OHP (hydroxyproline) levels as a surrogate 

marker of healing in their randomized control trial 

Table 7: Levels of evidence of the included articles in accordance with the JBI Levels of Evidence (APPENDIX C) (JBI = Joanna Briggs 

Institute; NA = Not Applicable). 

Evidence 
Level 

JBI Evidence Level Study Categories 

Effectiveness Diagnosis Prognosis 

1.a 0 0 0 

1.b 1 (237) 
10 (75, 85, 94, 130, 
144, 158, 176, 231, 

232, 234) 

35 (29, 31, 68, 74-76, 81, 83, 85, 87, 94, 97, 100, 102, 
124, 132, 144, 158, 171, 175, 176, 179, 191, 195, 198, 
201, 203, 206, 230-236) 

1.c 12 (103, 105, 136, 163, 212, 238-244) NA NA 

1.d 0 NA NA 

2.a 0 0 0 

2.b 0 0 0 

2.c 0 NA NA 

2.d 0 NA NA 

3.a 0 0 0 

3.b 1 (159) 0 

50 (32, 46, 72, 73, 84, 88, 90, 91, 98, 104, 106, 109-
113, 118, 123, 125, 126, 128, 130, 138, 139, 141-143, 
148, 149, 154, 156, 161, 166, 184, 185, 187, 188, 194, 

197, 211, 213, 214, 216, 220, 274-279) 

3.c 3 (77, 232, 268) NA NA 

3.d 3 (151, 183, 269) NA NA 

3.e 

34 (31, 69, 75, 76, 84, 99, 102, 106, 109, 113, 114, 
116, 121, 122, 125, 130, 144, 149, 153, 158, 176, 
179, 185, 196, 198, 199, 201, 224, 234, 235, 270-

273) 

NA NA 

4.a 0 0 0 

4.b 0 0 2 (93, 151) 

4.c 0 NA NA 

4.d 1 (89) NA NA 

5.a 0 0 0 

5.b 0 0 0 

5.c 

98 (65-67, 70, 71, 78-80, 82, 86, 92, 95, 96, 107, 
108, 115, 117, 119, 120, 127, 129, 131, 133-135, 
137, 140, 145-147, 150, 152, 155, 157, 160, 162, 
164, 165, 167-170, 172-174, 177, 178, 180-182, 

186, 189, 190, 192, 193, 200, 202, 204, 205, 207-
210, 215, 217-219, 221-223, 225-229, 245-267) 

4 (75, 85, 94, 231) 4 (101, 127, 131, 178) 

 
      Table 8: Study types of all included articles. 

Study Type Number (%) of Included Sources References of Included Sources 

Bench Research  99 (45%) 

65-67, 70, 71, 78-80, 82, 86, 92, 95, 96, 101, 107, 108, 115, 
117, 119, 120, 127, 129, 131, 133-135, 137, 140, 145-147, 150, 
152, 155, 157, 160, 162, 164, 165, 167-170, 172-174, 177, 178, 
180-182, 186, 189, 190, 192, 193, 200, 202, 204, 205, 207-210, 

215, 217-219, 221-223, 225-229, 245-267 

Observational Study 

Retrospective 52 (24%) 

32, 46, 72, 73, 84, 88, 90, 91, 98, 99, 104, 106, 109-113, 118, 
123, 126, 128, 130, 138, 139, 141-143, 148, 149, 154, 156, 159, 
161, 166, 171, 184, 187, 188, 194, 197, 211, 213, 214, 216, 220, 

224, 274-279 

Prospective 49 (22%) 
29, 31, 68, 69, 74-77, 81, 83, 85, 87, 94, 97, 100, 102, 114, 116, 
121, 122, 124, 125, 132, 144, 153, 158, 175, 176, 179, 191, 195, 

196, 198, 199, 201, 203, 206, 230-236, 268, 270-273 

Randomized Controlled Trial (RCT) 13 (6%) 103, 105, 136, 163, 212, 237-244 

Case-Controlled Study 6 (3%) 89, 93, 151, 183, 185, 269 

 

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9 

Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

investigating the effects of topical negative pressure (TNP) 

therapy on tissue oxygenation and wound healing in 

vascular foot wounds. 

A further 6 sources68,76,149,163,237,244 (all human participant 

studies) added a more systematic approach to the definition 

of healing than others through the implementation of 

grading systems/scales such as the Wagner Scale or the 

University of Texas classification system. Chen et al.,237 in 

their randomized controlled trial, defined a healed ulcer as 

Wagner Grade 0 (skin intact, but bony deformities lead to 

“foot at risk”282) and 1 (superficial ulcer). Lee et al.163 

evaluated residual limb incision healing using a modified 

Bates-Jensen Score (mBJS) assessment tool, scoring the 

following criteria from 1 to 5: amputation skin color, 

epithelization, amount of exudate, and the presence and 

volume of eschar. Higher scores therefore indicate worse 

healing. In fact, Jeon et al.,149 in their observational 

retrospective study, employed and compared five 

classification systems for diabetic foot ulcers (Meggitt-

Wagner classification; SINBAD [site, ischemia, neuropathy, 

bacterial infection, and depth] score; DEPA [depth of ulcer, 

extent of bacterial colonization, phase of ulcer, and 

association etiology] scoring system; UT [University of 

Texas] diabetic wound classification; DUSS [diabetic ulcer 

severity score]) to identify the “gold standard” prognostic 

classification system or optimum prediction tool for 

amputation. 

2.2: Non-Healing Definitions 

Over 80% (n = 183) of included sources provided no 

definition of impaired or non-healing wounds (Figure 3). In 

the limited sources (all were human participant studies) 

where a definition was stated, the identification of wound 

healing complications (Table 11), increase or no change in 

Table 9: Setting in which the included articles took place. Note that university includes university hospitals and some sources took place in more 

than one setting. 

Setting University Medical Center Research Center 
Governmental 
Organization 

Number of Included 
Sources 

190 66 35 1 

References 

29, 31, 32, 65-73, 75-81, 83-87, 
89-93, 95-108, 110-113, 115-
123, 125-157, 159, 161, 163-
177, 179-182, 184-195, 197, 
199-210, 212-229, 231-240, 
243, 244, 246-250, 252-255, 
259-269, 272, 273, 275, 277, 

278 

22, 29, 31, 32, 46, 72, 74, 76, 78, 82, 
85, 88, 90, 91, 93, 99, 100, 105, 109, 

114, 123, 125, 128-130, 136, 138, 
139, 148, 151, 154, 158, 167, 172, 

175, 179, 194-198, 201-203, 205-207, 
211, 214, 216, 228, 230, 232, 239-
242, 248, 253, 255, 257, 268, 273, 

274, 276, 277, 279 

94, 96, 124, 141, 150, 
155, 157, 160, 162, 169, 
173, 174, 178, 180, 183, 
184, 198, 200-202, 206, 
207, 215, 228, 241, 245, 
251, 255, 256, 258, 264, 

267, 268, 270, 271 

114 

 

Table 10: Number of included sources based in each country (some studies took place in more than one country). 

Country China USA India Japan Korea Turkey Taiwan UK Italy Germany 

No. 

56 (70, 81, 
95, 99, 102-

106, 108, 
115, 119, 
125, 126, 
128, 129, 
134, 139, 
140, 143, 
145, 150, 
168-170, 
172-174, 
177, 178, 
196, 203, 
208, 215, 
217, 218, 
220-229, 
245, 248, 
254, 255, 
259, 260, 
262, 267, 
273, 278) 

47 (78, 83, 85, 
88, 90, 92, 98, 
101, 108-112, 
127, 135, 137, 
146, 155, 156, 
160, 163, 171, 
179, 181, 182, 
194, 195, 199, 
204-207, 213, 
217, 219, 232, 
246, 247, 249, 
252, 257, 258, 
265, 266, 268, 

277, 279) 

13 (94, 
96, 117, 

124, 191, 
198, 232, 
233, 236, 
241, 251, 
256, 261) 

11 (29, 32, 
138, 153, 
158, 159, 
161, 193, 
211, 221, 

276) 

9 (70, 120, 
149, 155, 
157, 166, 
187, 188, 

216) 

9 (68, 84, 
89, 93, 97, 
142, 189, 
202, 275) 

7 (31, 
164, 165, 
167, 175, 
176, 237) 

7 (24, 67, 
148, 205, 
243, 255, 

281) 

7 (91, 
122, 
130, 
136, 
141, 
214, 
264) 

7 (71, 
131, 174, 
184, 234, 
254, 278) 

Country Canada Iraq Brazil Indonesia France Pakistan Cuba Netherlands Ireland Denmark 

No. 
5 (65, 66, 
102, 123, 

134) 

5 (67, 87, 231, 
250, 269) 

5 (78, 
132, 180, 
204, 274) 

5 (107, 
151, 239, 
240, 244) 

4 (86, 91, 
147, 201) 

4 (75, 120, 
230, 253) 

4 (183, 
268, 270, 

271) 

4 (46, 131, 
184, 235) 

3 (67, 
80, 86) 

3 (144, 
197, 253) 

Country Saudi Arabia Malaysia 
South 
Africa 

Iran Singapore Switzerland Austria Nigeria Poland 
Czech 

Republic 

No. 
3 (190, 236, 

261) 
3 (154, 210, 

261) 
3 (79, 

152, 186) 
3 (185, 

238, 272) 
2 (209, 
255) 

2 (118, 131) 
2 (131, 
184) 

2 (74, 100) 
2 (77, 
116) 

1 (148) 

Country Egypt Israel Thailand Lithuania Greece Norway Romania Lebanon Sweden Finland 

No. 1 (133) 1 (76) 1 (192) 1 (131) 1 (131) 1 (78) 1 (89) 1 (73) 1 (69) 1 (162) 

 

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10 

Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

wound size, or the need for operative interventions, 

explained non-healing in 4% (n = 9),83,109,112,163,179,195,206, 

216,276 1% (n = 2),83,158 and 4% (n = 9)32,109,118,179,194,195,206,216, 

273 of sources respectively. In none of the definitions were 

biomarkers used. Wound complications were defined 

differently depending on the source, as compiled in Table 

11. Of the 9 sources using wound complications to define 

non-healing, 67% (n = 6) explored healing in relation to the 

amputation surgical site.109,112,163,206,216,267 

In addition to major amputation, Furuyama et al.32 further 

defined ulcer non-healing in patients with critical limb 

ischemia by amputation or death. Contrastingly Kimura et 

al.158 defined worsened foot wounds only as wounds that 

had increased in size without amputation, with participants 

resulting in minor or major amputation, or all-cause death in 

the one-year study period being classified separately.  

In 10% (n = 22) of all included sources80,85,86,88,94-

96,106,121,127,144,145,169,178,183-185,205,207,234,253,279 both healing 

and non-healing definitions were considered not applicable 

given the content of the research. Laiva et al.,80 for example, 

explore the expression of pro-angiogenic factors 

(characteristic of wound healing) in human diabetic 

adipose-derived stem cells cultured on collagen scaffolds. 

Although this is investigating aspects of ulcer healing and is 

therefore relevant to the scoping review research question, 

it focuses on a specific cellular aspect of non-healing 

diabetic foot ulcers (DFUs), rather than in vivo whole ulcer 

healing (where several tissues and cells are involved). 

DISCUSSION 

This scoping review aimed to compile definitions of healing 

and non-healing found in the literature investigating 

biomarkers of healing in the tissues and structures of 

residual limbs of adults with amputation. The findings 

indicate a significant lack of standardized definitions of 

healing within the literature, with only one source242 

incorporating biomarkers (an objective measure rather than 

a subjective one) to define healing. Systematic methods for 

quantifying healing, such as pre-defined grading systems or 

scales like the Wagner Scale, were utilized in only 2% of the 

studies included. Moreover, these tools are generally 

designed for the assessment of open wound healing rather 

than surgical site healing. Similarly, definitions of non-

healing were either absent or inconsistently characterized 

by varying descriptions of wound complications.  

The review highlights a broader lack of consensus and 

standardization in defining both healing and non-healing, as 

current definitions are often superficial and predominantly 

based on visual and size-based assessments. These 

approaches fail to consider deeper tissue healing and 

mechanical properties essential for functionality, particularly 

in the context of prosthesis use. There is a critical need for 

more comprehensive, multidimensional definitions that 

incorporate objective measures like biomarkers and 

mechanical assessments, along with social and 

psychological evaluations, to more accurately reflect the 

complex nature of healing to guide future research and 

clinical practice more effectively. 

1: OVERALL SEARCH RESULTS 

No set number of articles should or should not be included 

in a review,283 and the number of included articles comes 

down to the search strategy and inclusion criteria. In this 

review, an arguably large number of articles (219) met the 

inclusion criteria, whereas in the similar work by Day et al.16 

on determinants of healing and readiness for prosthetic 

 

Figure 2: Frequency counts of healing definitions provided in all included sources, categorized by study types (OHP = hydroxyproline; DUSS 

= diabetic ulcer severity score; SINBAD = site, ischemia, neuropathy, bacterial infection, and depth; UT = University of Texas; DEPA = depth 

of ulcer, extent of bacterial colonization, phase of ulcer, and association etiology; PEDIS = perfusion, extent, depth, infection, and sensation; 

NA = not applicable). Note that the total frequency equates to greater than 219 (the number of total included sources) given that some 

included sources encapsulated two definitions in order to define healing (e.g. change in wound area and absence of wound complications).    

0 20 40 60 80 100

None provided

NA

Neovascularization

Complete epithelialization/healing

Absence of wound complications

Change in wound area/size

Complete healing documented in two consecutive visits and no amputation

DUSS, SINBAD, UT , Wagner, DEPA, PEDIS, or Bates-Jensen scores

Damaged tissue replaced by healthy connective tissue, forming a scar

Wound healing with no granulation tissue and minimal scar tissue observed

Assessed using OHP

Frequency Counts of Healing Definitions Provided in Included Sources 

RCT Case-Controlled Observational Prospective Observational Retrospective Bench Research

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11 

Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

fitting after transtibial amputation, 2,067 articles met the 

search strategy yet only 20 passed both screening stages. 

This difference is likely due to their inclusion criteria of 

transtibial amputation; in this review with the knowledge that 

the literature on healing on amputation specifically is low, 

the research question was expanded to wound healing of 

tissues like that of the lower limb residuum, thus broadening 

the number of search results. 

Of the 195 countries in the world, research from 40 of these 

countries was included in this review, several of which were 

LMICs (low-to-middle- income countries such as Cuba, 

Egypt, China, Malaysia, Nigeria, Thailand, and Pakistan).284 

Such global research allows us to expand findings across 

populations, regions, and cultures,285 reduces Western 

publication biases, and is critical in overcoming global 

health challenges286 like wound healing. It can be argued 

that the high number of countries from which research in 

this review originates highlights the global burden of wound 

healing. This is reinforced by the reported average of $2.8 

billion spent globally on wound healing in 2014.287 Guest et 

al.288 concluded that in the UK alone, between 2017 and 

2018, the cost to the NHS per healed wound ranged from 

£698 to £3,998 per patient, and that of an unhealed wound 

ranged from £1,719 to £5,976 per patient. 

Interestingly, Tricco et al.,289 in their scoping review of 

scoping review methodologies, revealed that 423 (86%) of 

the articles that met their inclusion criteria did not use a 

quality appraisal tool in their scoping review. However, it is 

well reported that critical (or quality) appraisal tools are a 

justifiable addition to a review to systematically assess the 

credibility of the research on which the results of the scoping 

review are then based.290 On the other hand, Tod et al.290 

further note that quality checklists, like the QualSyst tool, 

lack evidence to support their use; thus, quality assessment 

acts as an outcome measure, not an exclusionary criterion 

in this review. 

As detailed in the results section (Quality and Levels of 

Evidence) the high number of Effectiveness 5.c levels of 

evidence can be attributed to the 99 bench research studies 

(almost 50% of the included articles) that were included in 

data extraction. Of the 99 studies, 81 were rat or mouse 

studies, reinforcing the justification of bench research 

receiving the lowest level of evidence following the JBI 

levels of evidence. The lower number of higher-level 

evidence studies can be explained by the cost of studies 

such as RCTs (estimated to cost anywhere in the range of 

$43 to 103,254 per patient),291 and the common lag (as long 

as 17 years) in translating scientific discoveries (produced 

through bench research) into patient studies and thus 

patient benefit.292 

2: DEFINITIONS OF HEALING AND NON-HEALING 

In their review of complete wound closure definitions, Gould 

and Li28 recorded that complete/full/100% (re)epithe-

lialization or closure was the most common definition of 

healing. The same was noted here, of the 102 sources (47% 

of all included sources) that provided definitions of healing,  

30 were regarding epithelialization, and 61 were defined by 

changes in wound size/area. However, this assessment is 

limited in its applicability, particularly for surgical sites, such 

as amputation, which do not involve open wounds. The 

reliance on wound size to indicate healing, particularly 

through methods like measuring with disposable tapes,293 is 

problematic due to poor inter-rater and intra-rater reliability, 

its time-consuming nature, and issues inaccuracy.294-296 

Importantly, this focus on epithelialization alone does not 

capture the entirety of the healing process, as the 

proliferation phase, in which epithelialization occurs, is only 
 

 

Figure 3: Frequency counts of non-healing definitions provided in all included sources, categorized by study types (NA = not applicable). 

Note that the total frequency equates to greater than 219 (the number of total included sources) given that some sources encapsulated two 

definitions (for example MacDonald et al.83 used no change in wound size and presence of wound complications) in order to define non-

healing. 

0 50 100 150 200

Need for operative interventions including major amputation or re-amputation

Wound complications

Increase or no change in wound size

None provided

NA

Frequency Counts of Non-Healing Definitions Provided in Included Sources

RCT Case-Controlled Observational Prospective Observational Retrospective Bench Research

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Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

one of four phases of wound healing. Re-epithelialization 

occurs in the third phase, the proliferation phase (which 

takes place days to weeks after injury), where granulation 

tissue is formed, the epidermis is regenerated and 

neovascularization occurs.2 This phase is then followed by 

the fourth and final phase which occurs weeks to months 

after injury, remodeling, characterized by vascular 

maturation and regression, collagen remodeling, and the 

point at which a wound reaches its maximum strength and 

ultimate endpoint.2,3 In cutaneous tissue for example this 

final phase is marked by a collagenous scar. Therefore, it 

can be argued epithelialization suggests healing but does 

not indicate a fully healed wound. Particularly in the case of 

an amputation where the suture line may appear healed 

after re-epithelization has occurred, but the final phase of 

healing is still taking place below the skin and is likely 

heavily influenced by prosthetic use (and its subsequent 

mechanical loading).24 For example, Bramley et al.8 

conducted a study investigating changes in tissue 

composition and load response on 10 individuals with 

unilateral transtibial amputations, who had undergone the 

procedure between 1 and 35 years prior to the study (mean 

of 7.5 years) and were therefore classified as having mature 

residual limbs.25 The findings indicated a higher presence 

of adipose tissue infiltrating the muscle in residual limbs 

compared to intact contralateral limbs, suggesting muscle 

atrophy and adaptation post-amputation.8 Furthermore, 

intramuscular adipose content was found to correlate 

negatively with daily prosthetic socket use, reinforcing the 

idea that prosthetic use influences tissue composition in 

mature residual limbs, and likely has an even greater impact 

on early healing residual limbs. Therefore, a more 

comprehensive approach to defining healing should 

consider the deeper, ongoing processes beyond surface 

closure. 

Definitions of non-healing were more infrequent and when 

provided were complex, typically focusing on the 

identification of complications or deviations from normal 

healing. One possible reason for the limited reporting of 

non-healing definitions is the assumption by researchers 

that by defining healing, non-healing is implicitly understood 

as the opposite. Or perhaps the challenge of clearly defining 

non-healing is a symptom of the complexity of a chronic 

wound, its causes, and the variety of systemic (for example 

age,297, sex hormones,298 alcoholism,299 smoking,300 and 

nutrition301) and local (for example infection,302 

oxygenation,303 and venous sufficiency304) factors that 

impact healing.4 It is noteworthy that among the sources 

surveyed, studies focusing on amputation surgical sites 

Table 11: Wound healing complications stated in non-healing definitions coded for ‘wound complications’ (RCT = randomized controlled 

trial; CLTI = critical limb threatening ischemia; SSI = surgical site infection). 

Source Study Type Wound Type Non-Healing Definition Wound Complications 

Lee et al. 

(163) 
RCT Amputation 

Signs such as erythema, drainage, infection, incision breakdown, skin/fat necrosis, and/or 

tissue eschar. 

Majumdar 
et al. (179) 

Observational 
Prospective 

Surgical Site 
After Lower 
Extremity 
Revascularization 

Need for operative interventions for SSI or dehiscence, or new ulcerative wound or bypass 
graft infection. 

Nystrom et 
al. (195) 

Observational 
Prospective 

Surgical Site 
After Lower 
Extremity Soft 
Tissue Sarcoma 
Excision 

Any wound-related issue (necrosis, dehiscence, infection, seroma) treated by a return to the 
operating room, initiation of oral or intravenous (IV) antibiotics, intervention for seroma 
including aspiration, or prolonged wound packing or dressing changes greater than 120 days. 

Squiers et 
al. (206) 

Observational 
Prospective 

Lower Limb 
Amputation 

Development of necrosis; development of infection, including gangrene or abscess; ulceration 
occurring within or adjacent to the surgical wound; disruption or dehiscence of suture line; 
drainage or exudate expressed from the suture line; evidence of inflammatory response 
including swelling, cellulitis, or skin discoloration; hematoma formation; revision of the 
amputation to a more proximal level. 

MacDonald 
et al. (83) 

Observational 
Prospective 

Diabetic Foot 
Ulcer 

Pain, erythema, oedema, heat, purulent exudate, serous exudate with concurrent 
inflammation, delayed healing, discoloration of granulation tissue, friable granulation tissue, 
pocketing at the base of the wound, foul odor, and wound breakdown. 

Adams et 
al. (109) 

Observational 
Retrospective 

Transmetatarsal 
Amputation 

(1) revision of the amputation, defined as a return to the operating room for any reason; (2) 
postoperative infection, defined as any superficial or deep infection requiring oral antibiotics, 
admission to the hospital for intravenous antibiotics, and/or an unplanned return to the 
operating room; (3) chronic residual limb ulceration, defined as a non-healing wound at the 
surgical site requiring >4 weeks of wound care; (4) calcaneal gait, defined as any increased 
pressure at the plantar heel resulting in a pressure sore; (5) residual limb deformity, defined as 
a nonplantigrade foot; and (6) residual limb infarction, defined as ischemia or necrosis of the 
incision site. 

Alfawaz et 
al. (112) 

Observational 
Retrospective 

Below-Knee 
Amputation 

Separation or necrosis of skin, flap necrosis, or dry ischemic eschar formation. 

Morisaki et 
al. (276) 

Observational 
Retrospective 

Above or Below-
Knee Amputation 

Surgical site infection or wound dehiscence. 

Woo et al. 
(216) 

Observational 
Retrospective 

CLTI Patient 
Ulcer or 
Amputation 
Surgical Site 

Wounds requiring regular dressing and antibiotic treatment or surgical wound revision and 
additional surgery. 

 

 

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Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

were the primary providers of definitions for non-healing 

wound complications (6 of 9 included sources 
83,109,112,163,179,195,206,216,276). This trend may arise from the fact 

that traditional definitions of open wound healing, like 

epithelization or wound site evaluation, do not readily apply 

to closed surgical site wound types. Furthermore, 

individuals undergoing amputation often present with 

multiple comorbidities, such as diabetes and peripheral 

vascular diseases,19 and systemic factors for non-healing, 

such as smoking and alcohol use,305,306 which can 

negatively impact the healing process.20,299,300,307 For 

instance, Lind et al.306 retrospectively examined the impact 

of smoking on post-operative complications in 137 patients 

who had undergone primary above-knee or below-knee 

amputations, 44 of whom were cigarette smokers. The 

study found that smokers had a 2.5 times higher risk of 

infection and re-amputation compared to non-smokers, 

concluding that abstaining from smoking during the post-

operative healing phase is critical, as nicotine compromises 

cutaneous blood flow velocity and increases the risk of 

microthrombus formation.306 It can also be argued that 

healing complications such as infection or excessive 

oedema are primary barriers to prosthetic readiness, and 

thus of greater concern to prosthetists and rehabilitation 

professionals than indicators of healthy healing. Churilov et 

al.,308 for example, observed that the use of rigid dressings 

post-transtibial amputation, hypothesized to reduce swelling 

and promote healing, significantly shortened the time from 

amputation to casting or fitting of the first prosthesis, 

compared to traditional soft elastic dressings. In summary, 

identifying abnormal healing processes, particularly in the 

context of amputation, requires a more comprehensive 

approach than surface level visual assessments. A 

standardized system, tailored to specific wound types, 

would improve the clarity and consistency of healing and 

non-healing definitions. 

A biomarker, however, would allow both healing and non-

healing to be defined and monitored objectively and 

quantitatively. Unfortunately, only one included source242 

considered a biomarker in their definition of wound healing 

stating that they were to “demonstrate the effects of TNP on 

the healing of acute wounds of the foot by measuring the 

change in wound volume and collagen deposition”, enlisting 

OHP as a well-reported surrogate marker of collagen.242 In 

addition to deposition during the proliferative phase of 

healing, collagen, a key component of the extracellular 

matrix, induces platelet activation and aggregation in 

response to injury (phase one of healing), promotes 

fibroblast recruitment in the inflammatory stage, and 

influences remodeling of the extracellular matrix (ECM) 

increasing the tensile strength of the wound in the final 

remodeling/maturation phase.309 Chiang et al.242 further 

reported that wound volume reduction from day 0 to day 14 

of treatment was not significant (44.2% TNP vs 20.9% 

control; p = 0.15) suggesting that TNP did not expedite 

wound healing as expected. Similarly, the degree of 

collagen deposition (OHP content in tissue samples was 

expressed in micrograms of collagen per milligram of 

granulation tissue) on day 14 was also not significant 

between control and TNP-treated groups (58% TNP vs 

94.5% control; p = 0.32).242 In terms of absolute values, the 

TNP group noted a larger reduction in wound size, but the 

control group observed a greater increase in collagen 

deposition. This reinforces the notion that there is more to 

the healing process than simply the dimensions of the open 

wound.  Thus, biomarkers could provide a more nuanced 

and objective means of tracking both healing and non-

healing across all wound types, including surgical sites. 

Biomarkers have also been demonstrated in osteoarthritis 

research to indicate responses to loading tasks, providing 

valuable insights into joint health and predicting structural 

changes.310 This knowledge could be applied to monitoring 

the health of the residual limb, which undergoes adaptation 

during healing and early prosthetic use. For instance, in a 

posterior flap below-knee amputation, the gastrocnemius 

muscle forms a significant part of the muscle bulk covering 

the residual tibia. During prosthetic use, this muscle is 

subjected to forces in directions it would not experience in 

an intact limb, necessitating adaptation in response to these 

forces. 

Although not utilizing biomarkers, definitions in 6 

sources68,76,149,163,237,244 appeared to adopt a more 

systematic approach to assessing healing through the use 

of scales and classification systems such as the Wagner (or 

Meggitt-Wagner) system. Bar the modified Bates-Jensen 

(mBJS) adopted by Lee et al.,163 the classifications used 

apply only to diabetic open wounds or ulcers and again rely 

only on visual/surface level assessment external to the 

wound, limiting their relevance to surgical wounds. Diabetic 

foot ulcers (DFUs) account for much of the research on 

wound healing due to their global burden, with 80% of lower 

extremity amputations (LEAs) linked to DFUs.311 However, 

overemphasizing DFUs risks overlooking the specific needs 

of amputation sites, which require different criteria for 

assessing healing. The aforementioned mBJS which 

evaluates necrotic tissue topes, necrotic tissue volume, 

exudate type, skin color surrounding the wound, and 

epithelialization on a scale of 1 (best healing) to 5 (worst 

healing),312 although designed specifically for residuum 

healing assessment, is also limited to observer 

interpretation of the surgical site. Though not used in 

included sources, further surgical site healing classifications 

exist like the Centers for Disease Control (CDC) Surgical 

Wound Classification (SWC)313 and the Surgical Wound 

Assessment Tool (SWAT),314 but again they incorporate 

only a variety of subjective observations and are focused 

primarily on the identification of surgical site infections only. 

Despite being more holistic tools, these classifications still 

provide only subjective indicators of what is occurring under 

the skin and are therefore limited in truly assessing deep 

tissue healing; limitations that could be solved with more 

objective measures like biomarkers. 

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14 

Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

Interestingly, all the definitions of healing and non-healing 

focus purely on the physical components of wound healing. 

The optimal healing environments (OHE) framework 

however suggests that patient healing is best supported by 

addressing not just the physical, but the social, 

psychological, spiritual, and behavioral components of 

healthcare.315 Doering et al.,316 for example, observed that 

in 72 patients with bypass surgery, those with higher 

depressive symptom scores (indicating more symptoms) 

reported poorer emotional recovery (p < 0.001) and poorer 

physical recovery (p = 0.007) and achieved shorter walking 

distances (p < 0.001) than did patients with lower scores 

(indicating fewer symptoms). Furthermore, by 6 weeks after 

discharge, infections and impaired wound healing were 

more common among patients with higher depressive 

symptom scores (46%) than among patients with lower 

scores (19%, p = 0.03).316 Similarly, it is well known that 

amputation has psychological effects, with one review 

revealing that across 12 studies the prevalence of 

psychiatric disorders among amputees in India is in the 

range of 32% to 84%, including depression rates of 10.4% 

to 63% of the studied population, posttraumatic stress 

disorder rates of 3.3% to 56.3%, and phantom limb 

phenomenon rates of 14% to 92%.317 These symptoms of 

anxiety and depression reportedly do improve over 

time,317,318 yet no definitions of amputation healing detailed 

in this scoping review alluded to anything other than the 

physicality of the surgical site. Perhaps in the future, more 

effort should be made to consider more than the physical 

aspects when defining healing, providing a more holistic 

definition of healing.315,319,320 An amputation is a life-

changing event; with more objective and well-explained 

definitions of healing individuals with amputations may feel 

more comfortable about their surgical site healing journey 

which is currently limited by biases introduced by the timing 

of clinician visits and subjective surface level wound 

examination only.16,321  

Overall, the lack of provided definitions, irrespective of 

evidence level, wound type, or study type, raises concerns. 

For example, 13 included sources were RCTs (Table 8), the 

highest level of evidence, yet of these only 6 and 1 provided 

healing163163,237,238,241,242,244 and non-healing163 definitions 

respectively. Despite investigating healing, or an aspect of 

it, by not defining healing and non-healing the 

methodological rigor of the study is reduced by not providing 

a clear endpoint definition, and the belief that assessing 

wound healing is a purely visual process is perpetuated. As 

noted in previous studies16,321 the gap in the literature on 

healing definitions, particularly for amputation sites, remains 

unaddressed for over 20 years, despite its significance to 

patient outcomes. A shift toward more objective, 

comprehensive measures, incorporating biomarkers, 

psychological factors, and standardized definitions, would 

greatly enhance the study of wound healing in clinical 

settings. 

To develop a tailored and relevant scale for assessing 

wound healing in the context of residual limbs post-

amputation, the authors believe the following considerations 

should be made to ensure that it is comprehensive, 

objective, and clinically useful: 

1. Incorporate all four phases of healing, capturing both 

surface level and deeper tissue healing processes. 

2. Incorporate objective measures like biomarkers: 

• This will require identifying the most appropriate 

biomarkers for assessing post-amputation healing, 

potentially through a scoping review or bench 

research. For example, determining which 

biomarkers best assess the residual limb’s capacity 

to withstand prosthetic fitting could include indicators 

of healing complications like infection, inflammation, 

cell death, or response to mechanical loading. Song 

et al.322 identified that inflammatory markers such as 

white blood cell count, serum C-reactive protein 

levels, and erythrocyte sedimentation rate were 

significantly correlated with wound healing rates in 

diabetic patients. Additionally, thresholds or cut-off 

values for these biomarkers should be established to 

differentiate between healing and non-healing. For 

instance, a transcutaneous oxygen pressure 

(TcPO2) value below 40 mmHg has been associated 

with a 24% increased risk of healing complications in 

lower limb amputations, compared to values above 

40 mmHg.323 

 

• Techniques to quantify these biomarkers must be 

developed or adapted. This could involve 

quantitative imaging techniques such as ultrasound, 

which has been used to observe deeper tissue 

changes and predict the prognosis of pressure 

injuries,324 or innovative tools like wearable smart 

bandages capable of sensing wound pH, 

temperature, bioimpedance, glucose, oxygen, 

proteins, or uric acid in real-time.325 

3. Include subjective and psychosocial factors: 

• Psychological markers, such as anxiety, depression, 

and body image perception, should be addressed, 

as they influence overall recovery.316,317 A number of 

existing validated tools used in the lower limb 

amputee population are available such as the 

Hospital Anxiety and Depression Scale.326,327  

 

• Patient-reported outcomes (PROs), such as the 

Visual Analogue Scale (VAS) for pain328 and the 

Prosthetic Limb Users Survey of Mobility (PLUS-

M),329 can capture the patient’s perspective on pain, 

mobility, and comfort, offering deeper insights into 

functional recovery and prosthetic readiness. 

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Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

Research should explore which outcome measures 

most effectively reflect prosthetic readiness, perhaps 

through a pilot study investigating the effectiveness 

of different measurement tools in monitoring post-

amputation healing. The COMET (Core Outcome 

Measures in Effectiveness Trials) initiative provides 

a list of key outcome measures for studies of people 

undergoing major lower limb amputation for 

complications of peripheral vascular disease, 

including death, quality of life, mobility, and social 

integration/independence,330 which can serve as a 

foundation to be built upon with more objective 

measures like biomarkers. 

A multi-tiered grading system should be created, where 

each grade corresponds to specific milestones in the 

healing process, defined by clear criteria. For instance, 

Gethin et al.331 conducted a scoping review and identified 

normal wound bed temperature in chronic wounds as being 

between 30.2°C and 33.0°C. For each criterion, clear 

healing versus non-healing indicators should be 

established, distinguishing between successful healing and 

complications such as infection or excessive oedema. This 

will require participant research to identify objective 

indicators of both healthy (e.g., a decrease in temperature 

and pH332) and unhealthy (e.g., an increase in inflammatory 

markers333) healing processes. The classification system 

must undergo rigorous pilot testing and validation. This 

includes: 

• Reliability testing, ensuring high inter-rater and intra-

rater reliability through testing in diverse clinical 

settings. 
 

• Construct validity testing, comparing the system 

against known standards to confirm its accuracy. 

 

• Patient-centered validation to ensure that users’ 

opinions are incorporated during all stages of 

development to guarantee the scale addresses 

meaningful aspects of their recovery journey.334 

In the future, automation and streamlined assessment 

processes could be explored, for example, potentially 

incorporating wearable sensors for remote monitoring of 

residual limb health during healing. This could enhance the 

scale’s practicality and accessibility. It is also essential that 

the scale should undergo longitudinal tracking, allowing for 

continuous feedback and refinement. Regular updates or 

revisions should be made based on new research or clinical 

findings to reflect the evolving understanding of wound 

healing. By incorporating these elements, the scale will be 

robust, adaptable, and capable of providing both clinicians 

and patients with valuable insights into the healing process 

and readiness for prosthetic use. 

 

3: METHODOLOGICAL DISCUSSION 

3.1: Methodological Strengths 

A scoping review appears to be the most suitable approach 

to answering the research question due to its ability to 

comprehensively explore the extensive and unclear 

literature on impaired and healthy wound healing 

biomarkers and definitions, without restrictions on source 

types. In contrast, a systematic review would necessitate a 

more narrowly defined research question. 

A key strength of this review is simply the significance of the 

conclusions drawn. By highlighting both the lack of healing 

definitions and the limitations within provided definitions, 

this systematically implemented review reinforces the need 

for further research into objective measures to quantify 

healing. The sooner we can reach a consensus on the most 

appropriate definition of healing (both cutaneous and 

subcutaneous), the sooner we can identify or predict a 

healing/non-healing wound, and the sooner it can be 

prevented or treated.22 

3.2: Methodological Limitations 

Despite the implementation of an exhaustive search 

strategy, there is always a likelihood that some sources may 

have been missed. Therefore, it is important to remember 

that the results of the scoping review will guide future work; 

they will not influence healthcare policy, for example.  

A further limitation is the current lack of a second reviewer 

contradicting the JBI’s recommendation for a minimum of 

two reviewers to validate results, remove bias,35 and 

increase the number of relevant articles included in a 

review.335 However, given the nature of the authors’ 

resource constraints, only the primary author of this study 

could act as the reviewer, and the supervisory team acted 

as a verifier. Again, it is important to consider the purpose 

of the review;336 for example, is it impacting policy? If so, 

then it is particularly pertinent to ensure the methodology 

and the inclusion/exclusion criteria are rigorously justified 

and piloted. The review reported here, although thorough, 

is not intended to directly impact policy, and the lack of a 

second reviewer is perhaps more justified. Furthermore, this 

is not too dissimilar to peer-reviewed and published scoping 

reviews, with the work of Tricco et al.289 (a scoping review 

of scoping reviews) revealing that only 34% of reviewed 

scoping reviews included two or more independent 

reviewers. Yet simply introducing a standardized data 

extraction form, as the review reported here did, can 

minimize bias.35 

In the future, it would be beneficial to consider using multi-

lingual reviewers given that only sources in or translated into 

the English language could be investigated, potentially 

increasing Western publication biases.54,55 The choice was 

made to refrain from utilizing online translation software due 

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16 

Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

to the potential risk of semantic loss. Van Nes et al.337 for 

example recommend the use of a professional translator 

given that translation is an interpretative act in which 

meaning can be lost. However, this option is costly and falls 

beyond the scope of the research supporting this 

manuscript. Although including all study types ensures 

more relevant sources are captured, the inclusion of rodent 

studies and mathematical models can be questioned.  

In review studies, a balance between high precision 

(narrow) and high recall (broad) searches is necessary to 

ensure sufficient studies are captured by the search whilst 

the time required to screen all included articles is feasible.60  

As such, this step was deemed unfeasible; assuming 300 

articles were included with 100 references each, a further 

30,000 articles would need to be screened; this was 

considered not an option given the limited project timescale 

of the primary author.  

Please note that a registered and published protocol for this 

review is not available, which may influence the consistency 

and transparency of the review process.  

4: ETHICAL CONSIDERATIONS 

The use of grey literature in reviews is a contentious topic. 

Searching for it can be time-consuming and it lacks the 

validation peer-reviewed literature can provide; however, it 

can reduce publication bias given that it provides data that 

is not found in commercially published articles.338 Thus, this 

review did aim to include grey literature however all that was 

generated during the searches did not meet the inclusion 

criteria; often failing to provide a sufficiently clear 

methodology and clear ethical approval. 

RCTs are considered the highest level of evidence,280 

however, they are expensive, and funding is limited. They 

are often industry-funded and therefore more likely to report 

a statistically significant positive outcome than studies 

without industry funding.339 Thus, evidence level has not 

been used as an exclusionary criterion in this scoping 

review. It was a requirement, however, that all included 

articles, where applicable, clearly stated ethical approval 

and sought informed consent when human participants 

were involved.  

CONCLUSION 

The aim of this review was 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. Wound healing was 

predominantly characterized by epithelization and wound 

closure, including healing rates, or left undefined. Non-

healing was often poorly explained, typically assessed by 

the need for operative intervention including re-amputation 

or signs of impaired healing when defined. This review 

highlights shortcomings in current definitions of healing and 

non-healing, which are frequently absent or based on 

superficial assessments influenced by clinician 

perspectives. These definitions mistakenly equate wound 

appearance and size with healing at deeper tissue levels, 

neglecting to account for the mechanical properties of the 

tissue that are critical, particularly in tissue subjected to 

loading during lower limb prosthesis use. This underscores 

the need for a more comprehensive approach to wound 

healing assessment, integrating biomarkers and potentially 

incorporating social and psychological evaluations, as a 

patient's environment significantly impacts their healing 

process. Before we can enhance wound management both 

before and after amputation and expedite the return to daily 

activities, it is essential to establish a clear consensus on 

what defines the healing and non-healing processes. 

ACKNOWLEDGEMENTS 

The author of this article would like to express appreciation to the 

Strathclyde Body Device Interface Mechanobiology Research 

Group for their assistance in the discussion of the review’s 

methodology. 

DECLARATION OF CONFLICTING INTERESTS 

The author has no conflicts of interest to declare. 

AUTHORS CONTRIBUTION 

• Hannelore Williams-Reid: the primary author of the 

manuscript, undertook the scoping review and prepared the 

final manuscript as part of a 4-year PhD program.  

• Arjan Buis: the primary PhD supervisor, assisted in developing 

the scoping review methodology and preparing the manuscript 

for publication. 

• Anton Johannesson: the secondary PhD supervisor, assisted 

in developing the scoping review methodology and preparing 

the manuscript for publication. 

 

All authors have read and approved the final version of the 

manuscript. 

 

SOURCES OF SUPPORT 

The PhD project under which this scoping review/manuscript falls 

is funded by the UKRI EPSRC as part of the Centre of Doctoral 

Training (CDT) in Prosthetics and Orthotics (P&O) (studentship 

2755854 "Wound management and early prosthetic rehabilitation" 

within project EP/S02249X/1) and by Össur. 

REFERENCES 

1.Herman TF, Bordoni B. Wound Classification. Wound 

Classification [Internet]. StatPearls. 2024; [cited 2024, July 5]. 

Available from: https://www.ncbi.nlm.nih.gov/books/NBK554456/ 

2.Wallace HA BB, Zito PM. Wound Healing Phases [Internet]. 

StatPearls. 2023; [cited 2024, July 5]. Available from: 

https://www.ncbi.nlm.nih.gov/books/NBK470443/ 

3.Stroncek JD, Reichert WM. Overview of wound healing in 

different tissue types. In: Reichert WM, editor. Indwelling neural 

https://doi.org/10.33137/cpoj.v7i2.43715
https://www.ncbi.nlm.nih.gov/books/NBK554456/
https://www.ncbi.nlm.nih.gov/books/NBK470443/


 

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Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

implants: Strategies for contending with the in Vivo Environment. 

Boca Raton (FL): CRC Press/Taylor & Francis; 2008. Chapter 1. 

Available from: https://www.ncbi.nlm.nih.gov/books/NBK3938/ 

4.Guo S, Dipietro LA. Factors affecting wound healing. J Dent Res. 

2010;89(3):219-29. DOI:10.1177/0022034509359125  

5.Armstrong DG, Meyr AJ. Risk factors for impaired wound healing 

and wound complications. Wolters Kluwer; 2023 [Available from: 

https://www.uptodate.com/contents/risk-factors-for-impaired-

wound-healing-and-wound-complications 

6.Kumar D, Singh S, Shantanu K, Goyal R, Kushwaha NS, Gupta 

AK, et al. Need of revision of lower limb amputations in a north 

Indian tertiary care centre. J Clin Diagn Res. 2015;9(12):Rc01-3. 

DOI:10.7860/jcdr/2015/16385.6886  

7.Choo YJ, Kim DH, Chang MC. Amputation stump management: 

A narrative review. World J Clin Cases. 2022;10(13):3981-8. 

DOI:10.12998/wjcc.v10.i13.3981  

8.Wound management clinical practice guidelines tissue viability 

service [Internet]. Trust ELNF. 2019; [cited 2024, July 5]. Available 

from:https://www.elft.nhs.uk/sites/default/files/Wound%20Manage

ment%20Guidelines%206.0.pdf 

9.Black JM, Brindle CT, Honaker JS. Differential diagnosis of 

suspected deep tissue injury. Int Wound J. 2016;13(4):531-9. 

DOI:10.1111/iwj.12471  

10.Peart J. The aetiology of deep tissue injury: A literature review. 

Br J Nurs. 2016;25(15):840-3. DOI:10.12968/bjon.2016.25.15.840 

11.Johannesson A, Larsson GU, Oberg T, Atroshi I. Comparison of 

vacuum-formed removable rigid dressing with conventional rigid 

dressing after transtibial amputation: Similar outcome in a 

randomized controlled trial involving 27 patients. Acta Orthop. 

2008;79(3):361-9. DOI:10.1080/17453670710015265  

12.Miller TA, Paul R, Forthofer M, Wurdeman SR. Impact of time to 

receipt of prosthesis on total healthcare costs 12 months 

postamputation. Am J Phys Med Rehabil. 2020;99(11):1026-31. 

DOI:10.1097/phm.0000000000001473  

13.Geertzen JH, Martina JD, Rietman HS. Lower limb amputation. 

Part 2: Rehabilitation--a 10 year literature review. Prosthet Orthot 

Int. 2001;25(1):14-20. DOI:10.1080/03093640108726563  

14.Singh RK, Prasad G. Long-term mortality after lower-limb 

amputation. Prosthet Orthot Int. 2016;40(5):545-51. 

DOI:10.1177/0309364615596067  

15.Pran L, Harnanan D, Baijoo S, Short A, Cave C, Maharaj R, et 

al. Major lower limb amputations: Recognizing pitfalls. Cureus. 

2021;13(8):e16972. DOI:10.7759/cureus.16972  

16.Day JD, Dionne CP, James S, Wang H. Determinants of healing 

and readiness for prosthetic fitting after transtibial amputation: 

Integrative literature review. Prosthet Orthot Int. 2023;47(1):43-53. 

DOI:10.1097/pxr.0000000000000163  

17.Optimising the timing for prosthetic fitting [Internet]. Bush & Co. 

2024; [cited 2024, July 5]. Available from: 

https://www.bushco.co.uk/news/optimal-time-for-fitting-a-

prosthetic.html 

18.Turner S, Belsi A, McGregor AH. Issues faced by prosthetists 

and physiotherapists during lower-limb prosthetic rehabilitation: A 

thematic analysis. Front Rehabil Sci. 2021;2:795021. 

DOI:10.3389/fresc.2021.795021  

19.Molina CA, Faulk J. Lower extremity amputation [Internet]. 

StatPearls Publishing. 2022; [cited 2024, July 5].  Available from: 

https://www.ncbi.nlm.nih.gov/books/NBK546594/ 

20.Spampinato SF, Caruso GI, De Pasquale R, Sortino MA, Merlo 

S. The treatment of impaired wound healing in diabetes: Looking 

among old drugs. Pharmaceuticals (Basel). 2020;13(4). 

DOI:10.3390/ph13040060  

21.Focus Area: Biomarkers [Internet]. FDA (U.S. Food and Drug 

Administration). 2022; [cited 2024, July 5].  Available from: 

https://www.fda.gov/science-research/focus-areas-regulatory-

science-report/focus-area-biomarkers 

22.Lindley LE, Stojadinovic O, Pastar I, Tomic-Canic M. Biology 

and biomarkers for wound healing. Plast Reconstr Surg. 

2016;138(3 Suppl):18s-28s. DOI:10.1097/prs.0000000000002682  

23.Strimbu K, Tavel JA. What are biomarkers? Curr Opin HIV AIDS. 

2010;5(6):463-6. DOI:10.1097/COH.0b013e32833ed177  

24.Bramley JL, Worsley PR, Bader DL, Everitt C, Darekar A, King 

L, et al. Changes in tissue composition and load response after 

transtibial amputation indicate biomechanical adaptation. Ann 

Biomed Eng. 2021;49(12):3176-88. DOI:10.1007/s10439-021-

02858-0  

25.Sanders JE, Fatone S. Residual limb volume change: 

systematic review of measurement and management. J Rehabil 

Res Dev. 2011;48(8):949-86. DOI:10.1682/jrrd.2010.09.0189  

26.Patel S, Maheshwari A, Chandra A. Biomarkers for wound 

healing and their evaluation. J Wound Care. 2016;25(1):46-55. 

DOI:10.12968/jowc.2016.25.1.46  

27.Bhutda S, Surve MV, Anil A, Kamath K, Singh N, Modi D, et al. 

Histochemical Staining of Collagen and Identification of Its 

Subtypes by Picrosirius Red Dye in Mouse Reproductive Tissues. 

Bio Protoc. 2017;7(21):e2592. DOI:10.21769/BioProtoc.2592  

28.Gould L, Li WW. Defining complete wound closure: Closing the 

gap in clinical trials and practice. Wound Repair Regen. 

2019;27(3):201-24. DOI:10.1111/wrr.12707  

29.Hata Y, Iida O, Okamoto S, Ishihara T, Nanto K, Tsujumura T, 

et al. Additional risk stratification using local and systemic factors 

for patients with critical limb ischaemia undergoing endovascular 

therapy in the Wi-Fi era. Eur J Vasc Endovasc Surg. 

2019;58(4):548-55. DOI:10.1016/j.ejvs.2019.06.005  

30.Furuyama T, Yamashita S, Yoshiya K, Kurose S, Yoshino S, 

Nakayama K, et al. The Controlling nutritional status score is 

significantly associated with complete ulcer healing in patients with 

critical limb ischemia. Ann Vasc Surg. 2020;66:510-7. 

DOI:10.1016/j.avsg.2019.12.031  

31.Hung SY, Tsai JS, Yeh JT, Chen KH, Lin CN, Yang HM, et al. 

Amino acids and wound healing in people with limb-threatening 

diabetic foot ulcers. J Diabetes Complications. 

2019;33(10):107403. DOI:10.1016/j.jdiacomp.2019.06.008  

https://doi.org/10.33137/cpoj.v7i2.43715
https://www.ncbi.nlm.nih.gov/books/NBK3938/
https://www.uptodate.com/contents/risk-factors-for-impaired-wound-healing-and-wound-complications
https://www.uptodate.com/contents/risk-factors-for-impaired-wound-healing-and-wound-complications
https://www.elft.nhs.uk/sites/default/files/Wound%20Management%20Guidelines%206.0.pdf
https://www.elft.nhs.uk/sites/default/files/Wound%20Management%20Guidelines%206.0.pdf
https://www.bushco.co.uk/news/optimal-time-for-fitting-a-prosthetic.html
https://www.bushco.co.uk/news/optimal-time-for-fitting-a-prosthetic.html
https://www.ncbi.nlm.nih.gov/books/NBK546594/
https://www.fda.gov/science-research/focus-areas-regulatory-science-report/focus-area-biomarkers
https://www.fda.gov/science-research/focus-areas-regulatory-science-report/focus-area-biomarkers


 

18 

Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

32.Furuyama T, Onohara T, Yamashita S, Yoshiga R, Yoshiya K, 

Inoue K, et al. Prognostic factors of ulcer healing and amputation-

free survival in patients with critical limb ischemia. Vascular. 

2018;26(6):626-33. DOI:10.1177/1708538118786864  

33.Leaper DJ, Durani P. Topical antimicrobial therapy of chronic 

wounds healing by secondary intention using iodine products. Int 

Wound J. 2008;5(2):361-8. DOI:10.1111/j.1742-

481X.2007.00406.x  

34.Gosain A, DiPietro LA. Aging and wound healing. World J Surg. 

2004;28(3):321-6. DOI:10.1007/s00268-003-7397-6  

35.Peters MDJ, Marnie C, Tricco AC, Pollock D, Munn Z, Alexander 

L, et al. Updated methodological guidance for the conduct of 

scoping reviews. JBI Evid Synth. 2020;18(10):2119-26. 

DOI:10.11124/jbies-20-00167  

36.Pollock D, Davies EL, Peters MDJ, Tricco AC, Alexander L, 

McInerney P, et al. Undertaking a scoping review: A practical guide 

for nursing and midwifery students, clinicians, researchers, and 

academics. J Adv Nurs. 2021;77(4):2102-13. DOI:10.1111/jan. 

14743  

37.Pollock D, Peters MDJ, Khalil H, McInerney P, Alexander L, 

Tricco AC, et al. Recommendations for the extraction, analysis, and 

presentation of results in scoping reviews. JBI Evid Synth. 

2023;21(3):520-32. DOI:10.11124/jbies-22-00123  

38.Khalil H, Peters MD, Tricco AC, Pollock D, Alexander L, 

McInerney P, et al. Conducting high quality scoping reviews-

challenges and solutions. J Clin Epidemiol. 2021;130:156-60. 

DOI:10.1016/j.jclinepi.2020.10.009  

39.PRISMA for Scoping Reviews [Internet]. PRISMA. 2024; [cited 

2024, July 5]. Available from: http://www.prisma-

statement.org/Extensions/ScopingReviews?AspxAutoDetectCooki

eSupport=1 

40.Tricco AC, Lillie E, Zarin W, O'Brien KK, Colquhoun H, Levac D, 

et al. PRISMA extension for scoping reviews (PRISMA-ScR): 

Checklist and explanation. Ann Intern Med. 2018;169(7):467-73. 

DOI:10.7326/m18-0850  

41.O'Brien KK, Colquhoun H, Levac D, Baxter L, Tricco AC, Straus 

S, et al. Advancing scoping study methodology: a web-based 

survey and consultation of perceptions on terminology, definition 

and methodological steps. BMC Health Serv Res. 2016;16:305. 

DOI:10.1186/s12913-016-1579-z  

42.Hollander JE, Singer AJ, Valentine S. Comparison of wound 

care practices in pediatric and adult lacerations repaired in the 

emergency department. Pediatr Emerg Care. 1998;14(1):15-8. 

DOI:10.1097/00006565-199802000-00004  

43.Lindaman LM. Bone healing in children. Clin Podiatr Med Surg. 

2001;18(1):97-108. 

44.Canêo LF, Neirotti R. The importance of the proper definition of 

adulthood: What is and what is not included in a scientific 

publication. Braz J Cardiovasc Surg. 2017;32(1):60. 

DOI:10.21470/1678-9741-2016-0049  

45.Family Law Reform Act 1969 [Internet]. UK Public General Acts. 

1969; [cited 2024, July 5]. Available from: 

https://www.legislation.gov.uk/ukpga/1969/46/section/1 

46.Giesen LJ, van den Boom AL, van Rossem CC, den Hoed PT, 

Wijnhoven BP. Retrospective multicenter study on risk factors for 

surgical site infections after appendectomy for acute appendicitis. 

Dig Surg. 2017;34(2):103-7. DOI:10.1159/000447647  

47.Surgical site infections: Prevention and treatment [Internet]. 

NICE. 2020; [cited 2024, July 5]. Available from: 

https://www.nice.org.uk/guidance/ng125 

48.Marques R, Lopes M, Ramos P, Neves Amado J, Alves P. 

Prognostic factors for delayed healing of complex wounds in adults: 

A scoping review protocol. Nurs Rep. 2022;12(4):904-11. 

DOI:10.3390/nursrep12040087  

49.Bryda EC. The Mighty Mouse: the impact of rodents on 

advances in biomedical research. Mo Med. 2013;110(3):207-11. 

50.Tierney E, O'Rourke C, Fenton JE. What is the role of 'the letter 

to the editor'? Eur Arch Otorhinolaryngol. 2015;272(9):2089-93. 

DOI:10.1007/s00405-014-3289-7  

51.Prontosan for treating acute and chronic wounds [Internet]. 

NICE. 2022; [cited 2024, July 5]. Available from: 

https://www.nice.org.uk/guidance/mtg67 

52.Bekele F, Chelkeba L. Amputation rate of diabetic foot ulcer and 

associated factors in diabetes mellitus patients admitted to 

Nekemte referral hospital, western Ethiopia: Prospective 

observational study. J Foot Ankle Res. 2020;13(1):65. 

DOI:10.1186/s13047-020-00433-9  

53.Jenkins DA, Mohamed S, Taylor JK, Peek N, van der Veer SN. 

Potential prognostic factors for delayed healing of common, non-

traumatic skin ulcers: A scoping review. Int Wound J. 

2019;16(3):800-12. DOI:10.1111/iwj.13100  

54.Skopec M, Issa H, Reed J, Harris M. The role of geographic bias 

in knowledge diffusion: a systematic review and narrative 

synthesis. Res Integr Peer Rev. 2020;5:2. DOI:10.1186/s41073-

019-0088-0  

55.Mulimani P. Publication bias towards Western populations 

harms humanity. Nat Hum Behav. 2019;3(10):1026-7. 

DOI:10.1038/s41562-019-0720-5  

56.Gao H, Yous ML, Connelly D, Hung L, Garnett A, Hay ME, et al. 

Virtual team-based care planning with older persons in formal care 

settings: A scoping review protocol. BMJ Open. 

2021;11(11):e054900. DOI:10.1136/bmjopen-2021-054900  

57.Pham MT, Rajić A, Greig JD, Sargeant JM, Papadopoulos A, 

McEwen SA. A scoping review of scoping reviews: Advancing the 

approach and enhancing the consistency. Res Synth Methods. 

2014;5(4):371-85. DOI:10.1002/jrsm.1123  

58.Ut TB, Peta Ellen T, Michelle B-J, Keryln C, Emily H, Peter AL, 

et al. A scoping review of research in chronic wounds: Protocol. 

Wound Practice and Research. 2021;29(4). DOI:10.33235/wpr. 

29.4.234-237  

59.Simonsen T, Sturge J, Duff C. Healing architecture in 

healthcare: A scoping review. Herd. 2022;15(3):315-28. 

DOI:10.1177/19375867211072513  

60.Hanneke R, Asada Y, Lieberman L, Neubauer L, & Fagen M. 

The scoping review method: Mapping the literature in “structural 

change” public health interventions. In Sage Research Methods 

https://doi.org/10.33137/cpoj.v7i2.43715
http://www.prisma-statement.org/Extensions/ScopingReviews?AspxAutoDetectCookieSupport=1
http://www.prisma-statement.org/Extensions/ScopingReviews?AspxAutoDetectCookieSupport=1
http://www.prisma-statement.org/Extensions/ScopingReviews?AspxAutoDetectCookieSupport=1
https://www.legislation.gov.uk/ukpga/1969/46/section/1
https://www.nice.org.uk/guidance/ng125
https://www.nice.org.uk/guidance/mtg67


 

19 

Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

Cases Part 2. SAGE Publications, Ltd., 2017. 

https://doi.org/10.4135/9781473999008 

61.Leanne M. Kmet, Robert C. Lee, Cook LS. Standard 

quality assessment criteria for evaluating primary research 

papers from a variety of fields [Internet]. AHFMR. 2014;  

[cited 2024, July 5]. Available from: 

https://www.ihe.ca/download/standard_quality_assessment_criteri

a_for_evaluating_primary_research_papers_from_a_variety_of_fi

elds.pdf 

62.Maharaj S, Harding R. The needs, models of care, interventions 

and outcomes of palliative care in the Caribbean: A systematic 

review of the evidence. BMC Palliat Care. 2016;15:9. 

DOI:10.1186/s12904-016-0079-6  

63.Dewan P. Words versus pictures: Leveraging the research on 

visual communication. Partnership: The Canadian Journal of 

Library and Information Practice and Research. 2015;10. 

DOI:10.21083/partnership.v10i1.3137 

64.Williams-Reid H, Buis A, Johannesson A, Lechler K. Wound 

management, healing, and early prosthetic rehabilitation: a scoping 

review of biomarkers. 2023. Abstract from The Future of prosthetics 

and Orthotics- 2nd CDT P&O conference, Glasgow, United 

Kingdom. 

65.Abedin-Do A, Zhang Z, Douville Y, Méthot M, Bernatchez J, 

Rouabhia M. Engineering diabetic human skin equivalent for in vitro 

and in vivo applications. Front Bioeng Biotechnol. 2022;10:989888. 

DOI:10.3389/fbioe.2022.989888  

66.Abedin-Do A, Zhang Z, Douville Y, Méthot M, Rouabhia M. 

Effect of electrical stimulation on diabetic human skin fibroblast 

growth and the secretion of cytokines and growth factors involved 

in wound healing. Biology (Basel). 2021;10(7). 

DOI:10.3390/biology10070641  

67.Al-Rikabi AHA, Tobin DJ, Riches-Suman K, Thornton MJ. 

Dermal fibroblasts cultured from donors with type 2 diabetes 

mellitus retain an epigenetic memory associated with poor wound 

healing responses. Sci Rep. 2021;11(1):1474. 

DOI:10.1038/s41598-020-80072-z  

68.Altay FA, Kuzi S, Altay M, Ateş İ, Gürbüz Y, Tütüncü EE, et al. 

Predicting diabetic foot ulcer infection using the neutrophil-to-

lymphocyte ratio: a prospective study. J Wound Care. 

2019;28(9):601-7. DOI:10.12968/jowc.2019.28.9.601  

69.Bachar-Wikstrom E, Manchanda M, Bansal R, Karlsson M, 

Kelly-Pettersson P, Sköldenberg O, et al. Endoplasmic reticulum 

stress in human chronic wound healing: Rescue by 4-

phenylbutyrate. Int Wound J. 2021;18(1):49-61. 

DOI:10.1111/iwj.13525  

70.Bai H, Kyu-Cheol N, Wang Z, Cui Y, Liu H, Liu H, et al. 

Regulation of inflammatory microenvironment using a self-healing 

hydrogel loaded with BM-MSCs for advanced wound healing in rat 

diabetic foot ulcers. J Tissue Eng. 2020;11:2041731420947242. 

DOI:10.1177/2041731420947242 

71.Bayer A, Lammel J, Lippross S, Klüter T, Behrendt P, 

Tohidnezhad M, et al. Platelet-released growth factors induce 

psoriasin in keratinocytes: Implications for the cutaneous barrier. 

Ann Anat. 2017;213:25-32. DOI:10.1016/j.aanat.2017.04.002  

72.Brookes JDL, Jaya JS, Tran H, Vaska A, Werner-Gibbings K, 

D'Mello AC, et al. Broad-ranging nutritional deficiencies predict 

amputation in diabetic foot ulcers. Int J Low Extrem Wounds. 

2020;19(1):27-33. DOI:10.1177/1534734619876779  

73.Chahrour MA, Kharroubi H, Al Tannir AH, Assi S, Habib JR, 

Hoballah JJ. Hypoalbuminemia is associated with mortality in 

patients undergoing lower extremity amputation. Ann Vasc Surg. 

2021;77:138-45. DOI: 10.1016/j.avsg.2021.05.047 

74.Ezeani IU, Ugwu ET, Adeleye FO, Gezawa ID, Okpe IO, 

Enamino MI. Determinants of wound healing in patients 

hospitalized for diabetic foot ulcer: results from the MEDFUN study. 

Endocr Regul. 2020;54(3):207-16. DOI:10.2478/enr-2020-0023  

75.Farooque U, Lohano AK, Hussain Rind S, Rind MS, Sr., Karimi 

S, Jaan A, et al. Correlation of hemoglobin A1C with wagner 

classification in patients with diabetic foot. Cureus. 

2020;12(7):e9199. DOI:10.7759/cureus.9199  

76.Feldbrin Z, Omelchenko E, Lipkin A, Shargorodsky M. 

Osteopontin levels in plasma, muscles, and bone in patient with 

non-healing diabetic foot ulcers: A new player in wound healing 

process? J Diabetes Complications. 2018;32(8):795-8. 

DOI:10.1016/j.jdiacomp.2018.05.009  

77.Hohendorff J, Drozdz A, Borys S, Ludwig-Slomczynska AH, 

Kiec-Wilk B, Stepien EL, et al. Effects of negative pressure wound 

therapy on levels of angiopoetin-2 and other selected circulating 

signaling molecules in patients with diabetic foot ulcer. J Diabetes 

Res. 2019;2019:1756798. DOI:10.1155/2019/1756798  

78.Icli B, Wu W, Ozdemir D, Li H, Haemmig S, Liu X, et al. 

MicroRNA-135a-3p regulates angiogenesis and tissue repair by 

targeting p38 signaling in endothelial cells. Faseb j. 

2019;33(4):5599-614. DOI:10.1096/fj.201802063RR  

79.Jere SW, Houreld NN, Abrahamse H. Photobiomodulation 

activates the PI3K/AKT pathway in diabetic fibroblast cells in vitro. 

J Photochem Photobiol B. 2022;237:112590. DOI:10.1016/ 

j.jphotobiol.2022.112590  

80.Laiva AL, O'Brien FJ, Keogh MB. SDF-1α Gene-activated 

collagen scaffold restores pro-angiogenic wound healing features 

in human diabetic adipose-derived stem cells. Biomedicines. 

2021;9(2). DOI:10.3390/biomedicines9020160  

81.Li G, Zou X, Zhu Y, Zhang J, Zhou L, Wang D, et al. Expression 

and influence of matrix metalloproteinase-9/tissue inhibitor of 

metalloproteinase-1 and vascular endothelial growth factor in 

diabetic foot ulcers. Int J Low Extrem Wounds. 2017;16(1):6-13. 

DOI:10.1177/1534734617696728  

82.Liu Y, Wang F, Chen B. Anti-Inflammatory and antioxidant 

effects of chrysin mitigates diabetic foot ulcers. Int J Pharmacol. 

2023;19(1):122-30. DOI:10.3923/ijp.2023.122.130  

83.MacDonald A, Brodell JD, Jr., Daiss JL, Schwarz EM, Oh I. 

Evidence of differential microbiomes in healing versus non-healing 

diabetic foot ulcers prior to and following foot salvage therapy. J 

Orthop Res. 2019;37(7):1596-603. DOI:10.1002/jor.24279  

84.Metineren H, Dülgeroğlu TC. Comparison of the 

neutrophil/lymphocyte ratio and c-reactive protein levels in patients 

with amputation for diabetic foot ulcers. Int J Low Extrem Wounds. 

2017;16(1):23-8. DOI:10.1177/1534734617696729  

https://doi.org/10.33137/cpoj.v7i2.43715
https://doi.org/10.4135/9781473999008
https://www.ihe.ca/download/standard_quality_assessment_criteria_for_evaluating_primary_research_papers_from_a_variety_of_fields.pdf
https://www.ihe.ca/download/standard_quality_assessment_criteria_for_evaluating_primary_research_papers_from_a_variety_of_fields.pdf
https://www.ihe.ca/download/standard_quality_assessment_criteria_for_evaluating_primary_research_papers_from_a_variety_of_fields.pdf


 

20 

Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

85.Miller A, Jeyapalina S, Agarwal J, Mansel M, Beck JP. A 

preliminary, observational study using whole-blood RNA 

sequencing reveals differential expression of inflammatory and 

bone markers post-implantation of percutaneous osseointegrated 

prostheses. PLoS One. 2022;17(5):e0268977. 

DOI:10.1371/journal.pone.0268977  

86.Morey M, O'Gaora P, Pandit A, Hélary C. Hyperglycemia acts in 

synergy with hypoxia to maintain the pro-inflammatory phenotype 

of macrophages. PLoS One. 2019;14(8):e0220577. 

DOI:10.1371/journal.pone.0220577  

87.Neama NA, Darweesh M, Al-Obiadi AB. Prevalence and 

antibiotic susceptibility pattern in diabetic footulcer infection with Ev 

Alua Tion The Role Of biomarker Il-12 in disease. Biochem Cell 

Arch. 2018;18:2321-8.  

88.Newhall KA, Bekelis K, Suckow BD, Gottlieb DJ, Farber AE, 

Goodney PP, et al. The relationship of regional hemoglobin A1c 

testing and amputation rate among patients with diabetes. 

Vascular. 2017;25(2):142-8. DOI:10.1177/1708538116650099  

89.Raţiu IA, Raţiu CA, Miclăuş V, Boşca AB, Turan Kazancioğlu R, 

Constantin AM, et al. The pioneer use of a modified PRGF-

Endoret® technique for wound healing in a hemodialyzed diabetic 

patient in a terminal stage of renal disease. Rom J Morphol 

Embryol. 2021;62(2):465-73. DOI:10.47162/rjme.62.2.12  

90.Reiner MM, Khoury WE, Canales MB, Chmielewski RA, Patel K, 

Razzante MC, et al. Procalcitonin as a biomarker for predicting 

amputation level in lower extremity infections. J Foot Ankle Surg. 

2017;56(3):484-91. DOI:10.1053/j.jfas.2017.01.014 

91.Sapienza P, Mingoli A, Borrelli V, Brachini G, Biacchi D, Sterpetti 

AV, et al. Inflammatory biomarkers, vascular procedures of lower 

limbs, and wound healing. Int Wound J. 2019;16(3):716-23. 

DOI:10.1111/iwj.13086  

92.Sawaya AP, Jozic I, Stone RC, Pastar I, Egger AN, Stojadinovic 

O, et al. Mevastatin promotes healing by targeting caveolin-1 to 

restore EGFR signaling. JCI Insight. 2019;4(23). 

DOI:10.1172/jci.insight.129320  

93.Seçkin MF, Özcan Ç, Çamur S, Polat Ö, Batar S. Predictive 

factors and amputation level for reamputation in patients with 

diabetic foot: A retrospective case-control study. J Foot Ankle Surg. 

2022;61(1):43-7. DOI:10.1053/j.jfas.2021.06.006  

94.Sharma GR, Kumar V, Kanojia RK, Vaiphei K, Kansal R. Fast 

and slow myosin as markers of muscle regeneration in mangled 

extremities: a pilot study. Eur J Orthop Surg Traumatol. 

2019;29(7):1539-47. DOI:10.1007/s00590-019-02448-w  

95.Shen YY, Zhang RR, Liu QY, Li SY, Yi S. Robust temporal 

changes of cellular senescence and proliferation after sciatic nerve 

injury. Neural Regen Res. 2022;17(7):1588-95. DOI:10.4103/1673-

5374.330619  

96.Shetty S, Pavan G, Shetty A, Kumari S, Shetty P, Patil P. 

Molecular signatures in diabetic foot ulcer by integrated gene 

expression profiling via bioinformatics analysis. Biomedicine. 

2022;42:713-9. DOI:10.51248/.v42i4.1798  

97.Simsir IY, Sengoz Coskun NS, Akcay YY, Cetinkalp S. The 

relationship between blood hypoxia-inducible factor-1α, fetuin-A, 

fibrinogen, homocysteine, and amputation level. Int J Low Extrem 

Wounds. 2022;21(4):405-13. DOI:10.1177/1534734620948342  

98.Spoer DL, Shin SE, Kim KG, Haffner ZK, Linnartz KS, Attinger 

CE, et al. Perioperative evaluation of nutritional status to predict 

complications in patients with major lower extremity amputation. 

Wounds. 2023;35(3):59-65. DOI:10.25270/wnds/22070  

99.Sun H, Yang C, Liu X, Liang J, Geng H. Effectiveness of 

negative pressure wound therapy of diabetic foot ulcers using 

Periplaneta Americana (Kangfuxin liquid) irrigation. Int J Low 

Extrem Wounds. 2023:15347346231176917. 

DOI:10.1177/15347346231176917  

100.Ugwu E, Adeleye O, Gezawa I, Okpe I, Enamino M, Ezeani I. 

Predictors of lower extremity amputation in patients with diabetic 

foot ulcer: findings from MEDFUN, a multi-center observational 

study. J Foot Ankle Res. 2019;12:34. DOI:10.1186/s13047-019-

0345-y  

101.Walsh SA, Davis TA. Key early proinflammatory signaling 

molecules encapsulated within circulating exosomes following 

traumatic injury. J Inflamm (Lond). 2022;19(1):6. 

DOI:10.1186/s12950-022-00303-0  

102.Wang J, Tinney D, Grynyshyn M, Pickering JG, Power A, 

Dubois L, et al. Microcirculation surrounding end-stage human 

chronic skin wounds is associated with endoglin/CD146/ALK-1 

expression, endothelial cell proliferation and an absence of 

p16(Ink4a). Wound Repair Regen. 2023;31(3):321-37. 

DOI:10.1111/wrr.13081  

103.Wang T, Fan L, Liu J, Tao Y, Li X, Wang X, et al. Negative 

pressure wound therapy promotes wound healing by inhibiting 

inflammation in diabetic foot wounds: A role for NOD1 receptor. Int 

J Low Extrem Wounds. 2022:15347346221131844. 

DOI:10.1177/15347346221131844  

104.Xu S, Wang Y, Hu Z, Ma L, Zhang F, Liu P. Effects of 

neutrophil‐to‐lymphocyte ratio, serum calcium, and serum albumin 

on prognosis in patients with diabetic foot. Int Wound J. 2022;20. 

DOI:10.1111/iwj.14019  

105.Yang SL, Zhu LY, Han R, Sun LL, Dou JT. Effect of negative 

pressure wound therapy on cellular fibronectin and transforming 

growth factor-β1 expression in diabetic foot wounds. Foot Ankle Int. 

2017;38(8):893-900. DOI:10.1177/1071100717704940  

106.Yu XT, Wang F, Ding JT, Cai B, Xing JJ, Guo GH, et al. 

Tandem mass tag-based serum proteomic profiling revealed 

diabetic foot ulcer pathogenesis and potential therapeutic targets. 

Bioengineered. 2022;13(2):3171-82. DOI:10.1080/21655979.2022. 

2027173  

107.Yuniati R, Innelya I, Rachmawati A, Charlex HJM, Rahmatika 

A, Khrisna MB, et al. Application of topical sucralfate and topical 

platelet-rich plasma improves wound healing in diabetic ulcer Rats 

Wound Model. J Exp Pharmacol. 2021;13:797-806. 

DOI:10.2147/jep.S296767  

108.Zhang M, Zhang R, Li X, Cao Y, Huang K, Ding J, et al. CD271 

promotes STZ-induced diabetic wound healing and regulates 

epidermal stem cell survival in the presence of the pTrkA receptor. 

Cell Tissue Res. 2020;379(1):181-93. DOI:10.1007/s00441-019-

03125-4  

109.Adams BE, Edlinger JP, Ritterman Weintraub ML, Pollard JD. 

Three-year morbidity and mortality rates after nontraumatic 

https://doi.org/10.33137/cpoj.v7i2.43715


 

21 

Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

transmetatarsal amputation. J Foot Ankle Surg. 2018;57(5):967-71. 

DOI:10.1053/j.jfas.2018.03.047  

110.Aguirre A, Sharma K, Arora A, Humphries MD. Early ABI 

testing may decrease risk of amputation for patients with lower 

extremity ulcers. Ann Vasc Surg. 2022;79:65-71. 

DOI:10.1016/j.avsg.2021.08.015  

111.Ahn J, Raspovic KM, Liu GT, Lavery LA, La Fontaine J, 

Nakonezny PA, et al. Renal function as a predictor of early 

transmetatarsal amputation failure. Foot Ankle Spec. 

2019;12(5):439-51. DOI:10.1177/1938640018816371  

112.Alfawaz A, Kotha VS, Nigam M, Bekeny JC, Black CK, Tefera 

E, et al. Popliteal artery patency is an indicator of ambulation and 

healing after below-knee amputation in vasculopaths. Vascular. 

2022;30(4):708-14. DOI:10.1177/17085381211026498  

113.Aljarrah Q, Allouh MZ, Husein A, Al-Jarrah H, Hallak A, Bakkar 

S, et al. Transmetatarsal amputations in patients with diabetes 

mellitus: A contemporary analysis from an academic tertiary referral 

centre in a developing community. PLoS One. 

2022;17(11):e0277117. DOI:10.1371/journal.pone.0277117  

114.Anguiano-Hernandez YM, Contreras-Mendez L, de Los 

Angeles Hernandez-Cueto M, Muand Oz-Medina JE, Santillan-

Verde MA, Barbosa-Cabrera RE, et al. Modification of HIF-1α, NF-

aκB, IGFBP-3, VEGF and adiponectin in diabetic foot ulcers treated 

with hyperbaric oxygen. Undersea Hyperb Med. 2019;46(1):35-44.  

115.Ariyanti AD, Zhang J, Marcelina O, Nugrahaningrum DA, Wang 

G, Kasim V, et al. Salidroside-pretreated mesenchymal stem cells 

enhance diabetic wound healing by promoting paracrine function 

and survival of mesenchymal stem cells under hyperglycemia. 

Stem Cells Transl Med. 2019;8(4):404-14. DOI:10.1002/sctm.18-

0143  

116.Barć P, Antkiewicz M, Śliwa B, Baczyńska D, Witkiewicz W, 

Skóra JP. Treatment of critical limb ischemia by 

pIRES/VEGF165/HGF administration. Ann Vasc Surg. 

2019;60:346-54. DOI:10.1016/j.avsg.2019.03.013  

117.Begum F, Manandhar S, Kumar G, Keni R, Sankhe R, Gurram 

PC, et al. Dehydrozingerone promotes healing of diabetic foot 

ulcers: A molecular insight. J Cell Commun Signal. 2023;17(3):673-

88. DOI:10.1007/s12079-022-00703-0  

118.Berli MC, Wanivenhaus F, Kabelitz M, Götschi T, Böni T, 

Rancic Z, et al. Predictors for reoperation after lower limb 

amputation in patients with peripheral arterial disease. Vasa. 

2019;48(5):419-24. DOI:10.1024/0301-1526/a000796  

119.Bian J, Bao L, Gao X, Wen X, Zhang Q, Huang J, et al. 

Bacteria-engineered porous sponge for hemostasis and 

vascularization. J Nanobiotechnology. 2022;20(1):47. 

DOI:10.1186/s12951-022-01254-7  

120.Bibi S, Ahmad F, Alam MR, Ansar M, Yeou KS, Wahedi HM. 

lapachol-induced upregulation of sirt1/sirt3 is linked with improved 

skin wound healing in alloxan-induced diabetic mice. Iran J Pharm 

Res. 2021;20(3):419-30. DOI:10.22037/ijpr.2021.112722.13914  

121.Bramley JL, Worsley PR, Bostan LE, Bader DL, Dickinson AS. 

Establishing a measurement array to assess tissue tolerance 

during loading representative of prosthetic use. Med Eng Phys. 

2020;78:39-47. DOI:10.1016/j.medengphy.2020.01.011  

122.Campitiello F, Mancone M, Cammarota M, D'Agostino A, Ricci 

G, Stellavato A, et al. Acellular dermal matrix used in diabetic foot 

ulcers: Clinical outcomes supported by biochemical and histological 

analyses. Int J Mol Sci. 2021;22(13). DOI:10.3390/ijms22137085  

123.Chan AS, Montbriand J, Eisenberg N, Roche-Nagle G. 

Outcomes of minor amputations in patients with peripheral vascular 

disease over a 10-year period at a tertiary care institution. Vascular. 

2019;27(1):8-18. DOI:10.1177/1708538118797544  

124.Chaudhary N, Huda F, Roshan R, Basu S, Rajput D, Singh SK. 

Lower limb amputation rates in patients with diabetes and an 

infected foot ulcer: A prospective observational study. Wound 

Manag Prev. 2021;67(7):22-30.  

125.Chen L, Ma W, Covassin N, Chen D, Zha P, Wang C, et al. 

Association of sleep-disordered breathing and wound healing in 

patients with diabetic foot ulcers. J Clin Sleep Med. 2021;17(5):909-

16. DOI:10.5664/jcsm.9088  

126.Cheng P, Dong Y, Hu Z, Huang S, Cao X, Wang P, et al. 

Biomarker prediction of postoperative healing of diabetic foot 

ulcers: A retrospective observational study of serum albumin. 

Journal of Wound Ostomy & Continence Nursing. 2021;48(4):339-

44. DOI:10.1097/won.0000000000000780  

127.Chowdary AR, Maerz T, Henn D, Hankenson KD, Pagani CA, 

Marini S, et al. Macrophage-mediated PDGF activation correlates 

with regenerative outcomes following musculoskeletal trauma. Ann 

Surg. 2023;278(2):e349-e59. DOI:10.1097/sla.0000000000005704  

128.Das SK, Yuan YF, Li MQ. Predictors of delayed wound healing 

after successful isolated below-the-knee endovascular intervention 

in patients with ischemic foot ulcers. J Vasc Surg. 2018;67(4):1181-

90. DOI:10.1016/j.jvs.2017.08.077  

129.Ding Y, Cui L, Zhao Q, Zhang W, Sun H, Zheng L. Platelet-rich 

fibrin accelerates skin wound healing in diabetic mice. Ann Plast 

Surg. 2017;79(3):e15-e9. DOI:10.1097/sap.0000000000001091  

130.Dinoto E, Ferlito F, La Marca MA, Tortomasi G, Urso F, Evola 

S, et al. The role of early revascularization and biomarkers in the 

management of diabetic foot ulcers: A single center experience. 

Diagnostics (Basel). 2022;12(2). 

DOI:10.3390/diagnostics12020538  

131.Doulamis A, Doulamis N, Angeli A, Lazaris A, Luthman S, 

Jayapala M, et al. A non-invasive photonics-based device for 

monitoring of diabetic foot ulcers: Architectural/sensorial 

components & technical specifications. Inventions. 2021;6(2):27.  

132.Dutra LMA, Melo MC, Moura MC, Leme LAP, De Carvalho MR, 

Mascarenhas AN, et al. Prognosis of the outcome of severe 

diabetic foot ulcers with multidisciplinary care. J Multidiscip Healthc. 

2019;12:349-59. DOI:10.2147/jmdh.S194969  

133.El-Gizawy SA, Nouh A, Saber S, Kira AY. Deferoxamine-

loaded transfersomes accelerates healing of pressure ulcers in 

streptozotocin-induced diabetic rats. J Drug Deliv Sci Technol. 

2020;58:101732. DOI:10.1016/j.jddst.2020.101732 

134.Elliott CG, Wang J, Walker JT, Michelsons S, Dunmore-Buyze 

J, Drangova M, et al. Periostin and CCN2 scaffolds promote the 

wound healing response in the skin of diabetic mice. Tissue Eng 

Part A. 2019;25(17-18):1326-39. DOI:10.1089/ten.TEA.2018.0268  

https://doi.org/10.33137/cpoj.v7i2.43715


 

22 

Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

135.Escuin-Ordinas H, Liu Y, Sun L, Hugo W, Dimatteo R, Huang 

RR, et al. Wound healing with topical BRAF inhibitor therapy in a 

diabetic model suggests tissue regenerative effects. PLoS One. 

2021;16(6):e0252597. DOI:10.1371/journal.pone.0252597  

136.Ferroni L, Gardin C, De Pieri A, Sambataro M, Seganfreddo E, 

Goretti C, et al. Treatment of diabetic foot ulcers with Therapeutic 

Magnetic Resonance (TMR®) improves the quality of granulation 

tissue. Eur J Histochem. 2017;61(3):2800. DOI:10.4081/ejh. 

2017.2800  

137.Friedman A, Siewe N. Mathematical model of chronic dermal 

wounds in diabetes and obesity. Bull Math Biol. 2020;82(10):137. 

DOI:10.1007/s11538-020-00815-x  

138.Furuyama T, Yamashita S, Yoshiya K, Kurose S, Yoshino S, 

Nakayama K, et al. The controlling nutritional status score is 

significantly associated with complete ulcer healing in patients with 

critical limb ischemia. Ann Vasc Surg. 2020;66:510-7. 

DOI:10.1016/j.avsg.2019.12.031  

139.Gao C, Yang L, Ju J, Gao Y, Zhang K, Wu M, et al. Risk and 

prognostic factors of replantation failure in patients with severe 

traumatic major limb mutilation. Eur J Trauma Emerg Surg. 

2022;48(4):3203-10. DOI:10.1007/s00068-021-01876-w  

140.Gao R, Zhou P, Li Y, Li Q. High glucose-induced IL-7/IL-7R 

upregulation of dermal fibroblasts inhibits angiogenesis in a 

paracrine way in delayed diabetic wound healing. J Cell Commun 

Signal. 2023;17(3):1023-38. DOI:10.1007/s12079-023-00754-x  

141.Gazzaruso C, Gallotti P, Pujia A, Montalcini T, Giustina A, 

Coppola A. Predictors of healing, ulcer recurrence and persistence, 

amputation and mortality in type 2 diabetic patients with diabetic 

foot: a 10-year retrospective cohort study. Endocrine. 

2021;71(1):59-68. DOI:10.1007/s12020-020-02431-0  

142.Gülcü A, Etli M, Karahan O, Aslan A. Analysis of routine blood 

markers for predicting amputation/re-amputation risk in diabetic 

foot. Int Wound J. 2020;17(6):1996-2004. DOI:10.1111/iwj.13491  

143.Guo Z, Yue C, Qian Q, He H, Mo Z. Factors associated with 

lower-extremity amputation in patients with diabetic foot ulcers in a 

Chinese tertiary care hospital. Int Wound J. 2019;16(6):1304-13. 

DOI:10.1111/iwj.13190  

144.Hansen RL, Langdahl BL, Jørgensen PH, Petersen KK, 

Søballe K, Stilling M. Changes in periprosthetic bone mineral 

density and bone turnover markers after osseointegrated implant 

surgery: A cohort study of 20 transfemoral amputees with 30-month 

follow-up. Prosthet Orthot Int. 2019;43(5):508-18. 

DOI:10.1177/0309364619866599  

145.He FL, Qiu S, Zou JL, Gu FB, Yao Z, Tu ZH, et al. Covering 

the proximal nerve stump with chondroitin sulfate proteoglycans 

prevents traumatic painful neuroma formation by blocking axon 

regeneration after neurotomy in Sprague Dawley rats. J Neurosurg. 

2021;134(5):1599-609. DOI:10.3171/2020.3.Jns193202  

146.He S, Walimbe T, Chen H, Gao K, Kumar P, Wei Y, et al. 

Bioactive extracellular matrix scaffolds engineered with 

proangiogenic proteoglycan mimetics and loaded with endothelial 

progenitor cells promote neovascularization and diabetic wound 

healing. Bioact Mater. 2022;10:460-73. 

DOI:10.1016/j.bioactmat.2021.08.017  

147.Huon JF, Gaborit B, Caillon J, Boutoille D, Navas D. A murine 

model of Staphylococcus aureus infected chronic diabetic wound: 

A new tool to develop alternative therapeutics. Wound Repair 

Regen. 2020;28(3):400-8. DOI:10.1111/wrr.12802  

148.Husakova J, Bem R, Fejfarova V, Jirkovska A, Woskova V, 

Jarosikova R, et al. Factors influencing the risk of major amputation 

in patients with diabetic foot ulcers treated by autologous cell 

therapy. J Diabetes Res. 2022;2022:3954740. 

DOI:10.1155/2022/3954740  

149.Jeon BJ, Choi HJ, Kang JS, Tak MS, Park ES. Comparison of 

five systems of classification of diabetic foot ulcers and predictive 

factors for amputation. Int Wound J. 2017;14(3):537-45. 

DOI:10.1111/iwj.12642  

150.Ji X, Jin P, Yu P, Wang P. Autophagy ameliorates 

Pseudomonas aeruginosa-infected diabetic wounds by regulating 

the toll-like receptor 4/myeloid differentiation factor 88 pathway. 

Wound Repair Regen. 2023;31(3):305-20. DOI:10.1111/wrr.13074  

151.Junaidi F, Muradi A, Pratama D, Suhartono R, Kekalih A. 

Effectiveness of doppler ultrasonography as a predictor of wound 

healing after below-knee amputation for peripheral arterial disease. 

Chirurgia (Bucur). 2020;115(5):618-25. DOI:10.21614/chirurgia. 

115.5.618  

152.Kasowanjete P, Abrahamse H, Houreld NN. 

Photobiomodulation at 660 nm stimulates in vitro diabetic wound 

healing via the Ras/MAPK pathway. Cells. 2023;12(7). 

DOI:10.3390/cells12071080  

153.Katagiri T, Kondo K, Shibata R, Hayashida R, Shintani S, 

Yamaguchi S, et al. Therapeutic angiogenesis using autologous 

adipose-derived regenerative cells in patients with critical limb 

ischaemia in Japan: A clinical pilot study. Sci Rep. 

2020;10(1):16045. DOI:10.1038/s41598-020-73096-y  

154.Kee KK, Nair HKR, Yuen NP. Risk factor analysis on the 

healing time and infection rate of diabetic foot ulcers in a referral 

wound care clinic. J Wound Care. 2019;28(Sup1):S4-s13. 

DOI:10.12968/jowc.2019.28.Sup1.S4  

155.Kim BE, Goleva E, Hall CF, Park SH, Lee UH, Brauweiler AM, 

et al. Skin wound healing is accelerated by a lipid mixture 

representing major lipid components of chamaecyparis obtusa 

plant extract. J Invest Dermatol. 2018;138(5):1176-86. 

DOI:10.1016/j.jid.2017.11.039  

156.Kim KG, Mishu M, Zolper EG, Bhardwaj P, Rogers A, Dekker 

PK, et al. Nutritional markers for predicting lower extremity free 

tissue transfer outcomes in the chronic wound population. 

Microsurgery. 2023;43(1):51-6. DOI:10.1002/micr.30794  

157.Kim S, Piao J, Hwang DY, Park JS, Son Y, Hong HS. 

Substance P accelerates wound repair by promoting 

neovascularization and preventing inflammation in an ischemia 

mouse model. Life Sci. 2019;225:98-106. 

DOI:10.1016/j.lfs.2019.04.015  

158.Kimura T, Watanabe Y, Tokuoka S, Nagashima F, Ebisudani 

S, Inagawa K. Utility of skin perfusion pressure values with the 

society for vascular surgery wound, ischemia, and foot infection 

classification system. J Vasc Surg. 2019;70(4):1308-17. 

DOI:10.1016/j.jvs.2019.01.045  

https://doi.org/10.33137/cpoj.v7i2.43715


 

23 

Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

159.Kodama A, Komori K, Koyama A, Sato T, Ikeda S, Tsuruoka T, 

et al. Impact of serum zinc level and oral zinc supplementation on 

clinical outcomes in patients undergoing infrainguinal bypass for 

chronic limb-threatening ischemia. Circ J. 2022;86(6):995-1006. 

DOI:10.1253/circj.CJ-21-0832  

160.Kolumam G, Wu X, Lee WP, Hackney JA, Zavala-Solorio J, 

Gandham V, et al. IL-22R ligands IL-20, IL-22, and IL-24 promote 

wound healing in diabetic db/db Mice. PLoS One. 

2017;12(1):e0170639 DOI:10.1371/journal.pone.0170639  

161.Koyama A, Kodama A, Tsuruoka T, Fujii T, Sugimoto M, Banno 

H, et al. Zinc deficiency and clinical outcome after infrainguinal 

bypass grafting for critical limb ischemia. Circ Rep. 2020;2(3):167-

73. DOI:10.1253/circrep.CR-20-0003  

162.Kurkipuro J, Mierau I, Wirth T, Samaranayake H, Smith W, 

Kärkkäinen HR, et al. Four in one-combination therapy using live 

lactococcus lactis expressing three therapeutic proteins for the 

treatment of chronic non-healing wounds. PLoS One. 

2022;17(2):e0264775. DOI:10.1371/journal.pone.0264775  

163.Lee JV, Engel C, Tay S, DeSilva G, Desai K, Cashin J, et al. 

Impact of N-acetyl-cysteine on ischemic stumps following major 

lower extremity amputation: a pilot randomized clinical trial. Ann 

Surg. 2022;276(5):e302-e10. DOI:10.1097/sla.0000000000005389  

164.Lee Y-H, Lin S-J. Chitosan/PVA Hetero-composite hydrogel 

containing antimicrobials, perfluorocarbon nanoemulsions, and 

growth factor-loaded nanoparticles as a multifunctional dressing for 

diabetic wound healing: synthesis, characterization, and in vitro/in 

vivo evaluation. Pharmaceutics. 2022;14(3):537.  

165.Lee YH, Hong YL, Wu TL. Novel silver and nanoparticle-

encapsulated growth factor co-loaded chitosan composite hydrogel 

with sustained antimicrobility and promoted biological properties for 

diabetic wound healing. Mater Sci Eng C Mater Biol Appl. 

2021;118:111385. DOI:10.1016/j.msec.2020.111385  

166.Lee YJ, Ahn CM, Ko YG, Park KH, Lee JW, Lee SJ, et al. Skin 

perfusion pressure predicts early wound healing after endovascular 

therapy in chronic limb threatening ischaemia. Eur J Vasc 

Endovasc Surg. 2021;62(6):909-17. 

DOI:10.1016/j.ejvs.2021.08.030  

167.Leu JG, Chiang MH, Chen CY, Lin JT, Chen HM, Chen YL, et 

al. Adenine accelerated the diabetic wound healing by PPAR delta 

and angiogenic regulation. Eur J Pharmacol. 2018;818:569-77. 

DOI:10.1016/j.ejphar.2017.11.027  

168.Li B, Zhou Y, Chen J, Wang T, Li Z, Fu Y, et al. Long non-

coding RNA H19 contributes to wound healing of diabetic foot ulcer. 

J Mol Endocrinol. 2020. DOI:10.1530/jme-19-0242  

169.Li C, Liu SY, Zhou LP, Min TT, Zhang M, Pi W, et al. 

Polydopamine-modified chitin conduits with sustained release of 

bioactive peptides enhance peripheral nerve regeneration in rats. 

Neural Regen Res. 2022;17(11):2544-50. DOI:10.4103/1673-

5374.339006  

170.Li G, Li D, Wu C, Li S, Chen F, Li P, et al. Homocysteine-

targeting compounds as a new treatment strategy for diabetic 

wounds via inhibition of the histone methyltransferase SET7/9. Exp 

Mol Med. 2022;54(7):988-98. DOI:10.1038/s12276-022-00804-1  

171.Li J, Arora S, Ikeoka K, Smith J, Dash S, Kimura S, et al. The 

utility of geriatric nutritional risk index to predict outcomes in chronic 

limb-threatening ischemia. Catheter Cardiovasc Interv. 

2022;99(1):121-33. DOI:10.1002/ccd.29949  

172.Li J, Chou H, Li L, Li H, Cui Z. Wound healing activity of 

neferine in experimental diabetic rats through the inhibition of 

inflammatory cytokines and nrf-2 pathway. Artif Cells Nanomed 

Biotechnol. 2020;48(1):96-106. DOI:10.1080/21691401.2019. 

1699814  

173.Li M, Li X, Gao Y, Yang Y, Yi C, Huang W, et al. Composite 

nanofibrous dressing loaded with Prussian blue and heparin for 

anti-inflammation therapy and diabetic wound healing. Int J Biol 

Macromol. 2023;242(Pt 3):125144. DOI:10.1016/j.ijbiomac.2023. 

125144  

174.Li S, Wang X, Chen J, Guo J, Yuan M, Wan G, et al. Calcium 

ion cross-linked sodium alginate hydrogels containing 

deferoxamine and copper nanoparticles for diabetic wound healing. 

Int J Biol Macromol. 2022;202:657-70. 

DOI:10.1016/j.ijbiomac.2022.01.080  

175.Lin BS, Chang CC, Tseng YH, Li JR, Peng YS, Huang YK. 

Using wireless near-infrared spectroscopy to predict wound 

prognosis in diabetic foot ulcers. Adv Skin Wound Care. 

2020;33(1):1-12. DOI:10.1097/01.ASW.0000613552.50065.d5  

176.Lin DS, Lee JK. Mobile Health-Based Thermometer for 

monitoring wound healing after endovascular therapy in patients 

with chronic foot ulcer: Prospective cohort study. JMIR Mhealth 

Uhealth. 2021;9(5):e26468. DOI:10.2196/26468  

177.Liu Y, Zhang X, Yang L, Zhou S, Li Y, Shen Y, et al. Proteomics 

and transcriptomics explore the effect of mixture of herbal extract 

on diabetic wound healing process. Phytomedicine. 

2023;116:154892. DOI:10.1016/j.phymed.2023.154892  

178.Luan H, Huiru g, Mo Z, Ren W, Guo H, Chu Z, et al. The bone 

alterations in hind limb amputation rats in vivo. Med Nov Technol 

Devices. 2020;8:100046. DOI:10.1016/j.medntd.2020.100046  

179.Majumdar M, Lella S, Hall RP, Sumetsky N, Waller HD, 

McElroy I, et al. Utilization of thromboelastography with platelet 

mapping to predict infection and poor wound healing in 

postoperative vascular patients. Ann Vasc Surg. 2022;87:213-24. 

DOI:10.1016/j.avsg.2022.03.008  

180.Manso G, Elias-Oliveira J, Guimarães JB, Pereira Í S, 

Rodrigues VF, Burger B, et al. Xenogeneic mesenchymal stem cell 

biocurative improves skin wounds healing in diabetic mice by 

increasing mast cells and the regenerative profile. Regen Ther. 

2023;22:79-89. DOI:10.1016/j.reth.2022.12.006  

181.McLaughlin PJ, Cain JD, Titunick MB, Sassani JW, Zagon IS. 

Topical naltrexone is a safe and effective alternative to standard 

treatment of diabetic wounds. Adv Wound Care (New Rochelle). 

2017;6(9):279-88. DOI:10.1089/wound.2016.0725  

182.Mehrvar S, Rymut KT, Foomani FH, Mostaghimi S, Eells JT, 

Ranji M, et al. Fluorescence imaging of mitochondrial redox state 

to assess diabetic wounds. IEEE J Transl Eng Health Med. 

2019;7:1800809. DOI:10.1109/jtehm.2019.2945323  

183.Mendoza-Marí Y, García-Ojalvo A, Fernández-Mayola M, 

Rodríguez-Rodríguez N, Martinez-Jimenez I, Berlanga-Acosta J. 

Epidermal growth factor effect on lipopolysaccharide-induced 

inflammation in fibroblasts derived from diabetic foot ulcer. Scars 

https://doi.org/10.33137/cpoj.v7i2.43715


 

24 

Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

Burn Heal. 2022;8:20595131211067380. DOI:10.1177/ 

20595131211067380  

184.Metcalf DG, Haalboom M, Bowler PG, Gamerith C, Sigl E, 

Heinzle A, et al. Elevated wound fluid pH correlates with increased 

risk of wound infection. Wound Med. 2019;26(1):100166. 

DOI:10.1016/j.wndm.2019.100166.  

185.Modaghegh MHS, Saberianpour S, Amoueian S, Shahri JJ, 

Rahimi H. The effect of redox signaling on extracellular matrix 

changes in diabetic wounds leading to amputation. Biochem 

Biophys Rep. 2021;26:101025. DOI:10.1016/j.bbrep.2021.101025  

186.Mokoena DR, Houreld NN, Dhilip Kumar SS, Abrahamse H. 

Photobiomodulation at 660 nm stimulates fibroblast differentiation. 

Lasers Surg Med. 2020;52(7):671-81. DOI:10.1002/lsm.23204  

187.Moon KC, Kim KB, Han SK, Jeong SH, Dhong ES. Risk factors 

for major amputation on hindfoot ulcers in hospitalized diabetic 

patients. Adv Wound Care (New Rochelle). 2019;8(5):177-85. 

DOI:10.1089/wound.2018.0814  

188.Moon KC, Kim SB, Han SK, Jeong SH, Dhong ES. Risk factors 

for major amputation in hospitalized diabetic patients with forefoot 

ulcers. Diabetes Res Clin Pract. 2019;158:107905. 

DOI:10.1016/j.diabres.2019.107905  

189.Mutlu HS, Erdoğan A, Tapul L. Autologously transplanted 

dermal fibroblasts improved diabetic wound in rat model. Acta 

Histochemica. 2020;122(5):151552. DOI:10.1016/j.acthis.2020. 

151552  

190.Nasrullah MZ. Caffeic acid phenethyl ester loaded PEG-PLGA 

nanoparticles enhance wound healing in diabetic rats. Antioxidants 

(Basel). 2022;12(1). DOI:10.3390/antiox12010060  

191.Nayak M, Nag HL, Nag TC, Digge V, Yadav R. Ultrastructural 

and histological changes in tibial remnant of ruptured anterior 

cruciate ligament stumps: a transmission electron microscopy and 

immunochemistry-based observational study. Musculoskelet Surg. 

2020;104(1):67-74. DOI:10.1007/s12306-019-00599-x  

192.Nensat C, Songjang W, Tohtong R, Suthiphongchai T, 

Phimsen S, Rattanasinganchan P, et al. Porcine placenta extract 

improves high-glucose-induced angiogenesis impairment. BMC 

Complement Med Ther. 2021;21(1):66. DOI:10.1186/s12906-021-

03243-z  

193.Nishikai-Yan Shen T, Kado M, Hagiwara H, Fujimura S, 

Mizuno H, Tanaka R. MMP9 secreted from mononuclear cell quality 

and quantity culture mediates STAT3 phosphorylation and 

fibroblast migration in wounds. Regen Ther. 2021;18:464-71. 

DOI:10.1016/j.reth.2021.10.003  

194.Norvell DC, Czerniecki JM. Risks and risk factors for ipsilateral 

re-amputation in the first year following first major unilateral 

dysvascular amputation. Eur J Vasc Endovasc Surg. 

2020;60(4):614-21. DOI:10.1016/j.ejvs.2020.06.026  

195.Nystrom LM, Mesko NW, Jin Y, Shah C, Spiguel A, White J, et 

al. Transcutaneous oximetry does not reliably predict wound-

healing complications in preoperatively radiated soft tissue 

sarcoma. Clin Orthop Relat Res. 2023;481(3):542-9. 

DOI:10.1097/corr.0000000000002279  

196.Ou S, Xu C, Yang Y, Chen Y, Li W, Lu H, et al. Transverse 

tibial bone transport enhances distraction osteogenesis and 

vascularization in the treatment of diabetic foot. Orthop Surg. 

2022;14(9):2170-9. DOI:10.1111/os.13416  

197.Pan X, You C, Chen G, Shao H, Han C, Zhi L. Skin perfusion 

pressure for the prediction of wound healing in critical limb 

ischemia: A meta-analysis. Arch Med Sci. 2018;14(3):481-7. 

DOI:10.5114/aoms.2016.62220  

198.Rajagopalan C, Viswanathan V, Rajsekar S, Selvaraj B, Daniel 

L. Diabetic foot ulcers—comparison of performance of ankle-

brachial index and transcutaneous partial oxygen pressure in 

predicting outcome. Int J Diabetes Dev Ctries. 2018;38(2):179-84. 

DOI:10.1007/s13410-017-0580-3  

199.Razjouyan J, Grewal GS, Talal TK, Armstrong DG, Mills JL, 

Najafi B. Does physiological stress slow down wound healing in 

patients with diabetes? J Diabetes Sci Technol. 2017;11(4):685-92. 

DOI:10.1177/1932296817705397  

200.Ridiandries A, Bursill C, Tan J. Broad-spectrum inhibition of the 

cc-chemokine class improves wound healing and wound 

angiogenesis. Int J Mol Sci. 2017;18(1). DOI:10.3390/ 

ijms18010155  

201.Salaun P, Desormais I, Lapébie FX, Rivière AB, Aboyans V, 

Lacroix P, et al. Comparison of ankle pressure, systolic toe 

pressure, and transcutaneous oxygen pressure to predict major 

amputation after 1 year in the COPART Cohort. Angiology. 

2019;70(3):229-36. DOI:10.1177/0003319718793566  

202.Senturk B, Demircan BM, Ozkan AD, Tohumeken S, Delibasi 

T, Guler MO, et al. Diabetic wound regeneration using heparin-

mimetic peptide amphiphile gel in db/db mice. Biomater Sci. 

2017;5(7):1293-303. DOI:10.1039/c7bm00251c  

203.Shi L, Xue J, Zhao W, Wei X, Zhang M, Li L, et al. The 

prognosis of diabetic foot ulcer is independent of age? a 

comparative analysis of the characteristics of patients with diabetic 

foot ulcer in different age groups: A cross-sectional study from 

China. Int J Low Extrem Wounds. 2022:15347346221125844. 

DOI:10.1177/15347346221125844  

204.Silva JC, Pitta MGR, Pitta IR, Koh TJ, Abdalla DSP. New 

peroxisome proliferator-activated receptor agonist (GQ-11) 

improves wound healing in diabetic mice. Adv Wound Care (New 

Rochelle). 2019;8(9):417-28. DOI:10.1089/wound.2018.0911  

205.Spreadborough PJ, Strong AL, Mares J, Levi B, Davis TA. 

Tourniquet use following blast-associated complex lower limb injury 

and traumatic amputation promotes end organ dysfunction and 

amplified heterotopic ossification formation. J Orthop Surg Res. 

2022;17(1):422. DOI:10.1186/s13018-022-03321-z  

206.Squiers JJ, Thatcher JE, Bastawros DS, Applewhite AJ, Baxter 

RD, Yi F, et al. Machine learning analysis of multispectral imaging 

and clinical risk factors to predict amputation wound healing. J Vasc 

Surg. 2022;75(1):279-85. DOI:10.1016/j.jvs.2021.06.478  

207.Strong AL, Spreadborough PJ, Dey D, Yang P, Li S, Lee A, et 

al. BMP Ligand Trap ALK3-Fc Attenuates osteogenesis and 

heterotopic ossification in blast-related lower extremity trauma. 

Stem Cells Dev. 2021;30(2):91-105. DOI:10.1089/scd.2020.0162  

208.Sun X, Wang X, Zhao Z, Chen J, Li C, Zhao G. Paeoniflorin 

accelerates foot wound healing in diabetic rats though activating 

the Nrf2 pathway. Acta Histochemica. 2020;122(8):151649. 

DOI:10.1016/j.acthis.2020.151649  

https://doi.org/10.33137/cpoj.v7i2.43715


 

25 

Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

209.Tan SS, Yeo XY, Liang ZC, Sethi SK, Tay SSW. Stromal 

vascular fraction promotes fibroblast migration and cellular viability 

in a hyperglycemic microenvironment through up-regulation of 

wound healing cytokines. Exp Mol Pathol. 2018;104(3):250-5. 

DOI:10.1016/j.yexmp.2018.03.007  

210.Tan WS, Arulselvan P, Ng SF, Mat Taib CN, Sarian MN, 

Fakurazi S. Improvement of diabetic wound healing by topical 

application of Vicenin-2 hydrocolloid film on Sprague Dawley rats. 

BMC Complement Altern Med. 2019;19(1):20. 

DOI:10.1186/s12906-018-2427-y  

211.Tanaka K, Tanaka S, Okazaki J, Mii S. Preoperative nutritional 

status is independently associated with wound healing in patients 

undergoing open surgery for ischemic tissue loss. Vascular. 

2021;29(6):897-904. DOI:10.1177/1708538120980216  

212.Vangaveti VN, Jhamb S, Hayes O, Goodall J, Bulbrook J, 

Robertson K, et al. Effects of vildagliptin on wound healing and 

markers of inflammation in patients with type 2 diabetic foot ulcer: 

a prospective, randomized, double-blind, placebo-controlled, 

single-center study. Diabetol Metab Syndr. 2022;14(1):183. 

DOI:10.1186/s13098-022-00938-2  

213.Vatankhah N, Jahangiri Y, Landry GJ, McLafferty RB, Alkayed 

NJ, Moneta GL, et al. Predictive value of neutrophil-to-lymphocyte 

ratio in diabetic wound healing. J Vasc Surg. 2017;65(2):478-83. 

DOI:10.1016/j.jvs.2016.08.108  

214.Vieceli Dalla Sega F, Cimaglia P, Manfrini M, Fortini F, 

Marracino L, Bernucci D, et al. Circulating biomarkers of endothelial 

dysfunction and inflammation in predicting clinical outcomes in 

diabetic patients with critical limb ischemia. Int J Mol Sci. 

2022;23(18). DOI:10.3390/ijms231810641  

215.Wang H, Wang X, Liu X, Zhou J, Yang Q, Chai B, et al. miR-

199a-5p Plays a pivotal role on wound healing via suppressing 

vegfa and rock1 in diabetic ulcer foot. Oxid Med Cell Longev. 

2022;2022:4791059. DOI:10.1155/2022/4791059  

216.Woo Y, Suh YJ, Lee H, Jeong E, Park SC, Yun SS, et al. 

TcPO2 value can predict wound healing time in clinical practice of 

CLTI patients. Ann Vasc Surg. 2023;91:249-56. 

DOI:10.1016/j.avsg.2022.11.020  

217.Wu M, Yu Z, Matar DY, Karvar M, Chen Z, Ng B, et al. Human 

amniotic membrane promotes angiogenesis in an oxidative stress 

chronic diabetic murine wound model. Adv Wound Care (New 

Rochelle). 2023;12(6):301-15. DOI:10.1089/wound.2022.0005  

218.Xiang X, Chen J, Jiang T, Yan C, Kang Y, Zhang M, et al. Milk-

derived exosomes carrying siRNA-KEAP1 promote diabetic wound 

healing by improving oxidative stress. Drug Deliv Transl Res. 

2023;13(9):2286-96. DOI:10.1007/s13346-023-01306-x  

219.Yan J, Tie G, Wang S, Tutto A, DeMarco N, Khair L, et al. 

Diabetes impairs wound healing by Dnmt1-dependent 

dysregulation of hematopoietic stem cells differentiation towards 

macrophages. Nat Commun. 2018;9(1):33. DOI:10.1038/s41467-

017-02425-z  

220.Yang S, Gu Z, Lu C, Zhang T, Guo X, Xue G, et al. Neutrophil 

extracellular traps are markers of wound healing impairment in 

patients with diabetic foot ulcers treated in a multidisciplinary 

setting. Adv Wound Care (New Rochelle). 2020;9(1):16-27. 

DOI:10.1089/wound.2019.0943  

221.Yang X, Mathis BJ, Huang Y, Li W, Shi Y. KLF4 Promotes 

diabetic chronic wound healing by suppressing Th17 cell 

differentiation in an MDSC-dependent manner. J Diabetes Res. 

2021;2021:7945117. DOI:10.1155/2021/7945117  

222.Yang Y, Hu H, Wang W, Duan X, Luo S, Wang X, et al. The 

identification of functional proteins from amputated lumbricus 

Eisenia fetida on the wound healing process. Biomed 

Pharmacother. 2017;95:1469-78. 

DOI:10.1016/j.biopha.2017.09.049  

223.Zhang F, Liu Y, Wang S, Yan X, Lin Y, Chen D, et al. 

Interleukin-25-mediated-IL-17RB upregulation promotes 

cutaneous wound healing in diabetic mice by improving endothelial 

cell functions. Front Immunol. 2022;13:809755. 

DOI:10.3389/fimmu.2022.809755  

224.Zhang S, Wang S, Xu L, He Y, Xiang J, Tang Z. Clinical 

outcomes of transmetatarsal amputation in patients with diabetic 

foot ulcers treated without revascularization. Diabetes Ther. 

2019;10(4):1465-72. DOI:10.1007/s13300-019-0653-z  

225.Zhang Y, Jiang W, Kong L, Fu J, Zhang Q, Liu H. PLGA@IL-8 

nanoparticles-loaded acellular dermal matrix as a delivery system 

for exogenous MSCs in diabetic wound healing. Int J Biol 

Macromol. 2023;224:688-98. DOI:10.1016/j.ijbiomac.2022.10.157  

226.Zhao Y, Luo L, Huang L, Zhang Y, Tong M, Pan H, et al. In situ 

hydrogel capturing nitric oxide microbubbles accelerates the 

healing of diabetic foot. J Control Release. 2022;350:93-106. 

DOI:10.1016/j.jconrel.2022.08.018  

227.Zhao Y, Wang X, Yang S, Song X, Sun N, Chen C, et al. 

Kanglexin accelerates diabetic wound healing by promoting 

angiogenesis via FGFR1/ERK signaling. Biomed Pharmacother. 

2020;132:110933. DOI:10.1016/j.biopha.2020.110933  

228.Zheng Z, Liu Y, Yang Y, Tang J, Cheng B. Topical 1% 

propranolol cream promotes cutaneous wound healing in 

spontaneously diabetic mice. Wound Repair Regen. 

2017;25(3):389-97. DOI:10.1111/wrr.12546  

229.Zhu Z, Wang L, Peng Y, Xiaoying C, Zhou L, Jin Y, et al. 

Continuous self‐oxygenated double‐layered hydrogel under natural 

light for real‐time infection monitoring, enhanced photodynamic 

therapy, and hypoxia relief in refractory diabetic wounds healing. 

Adv Funct Mater. 2022;32. DOI:10.1002/adfm.202201875  

230.Dur-E-Sameen Msskkhksmiazk. Exploring association of 

anemia with diabetic foot ulcer and its impact on disease outcome 

in a tertiary care hospital. Pak J Med Health Sci. 2023;16(12):406. 

DOI:10.53350/pjmhs20221612406  

231.Salih K, Faraj YF, Mohammed I. Salivary matrix 

metalloproteinase-8 indicate the severity of diabetic foot ulcer. Int J 

Biochem Cell Biol. 2020;18:1543-8.  

232.Kevin L, Jagadeesh M, Priscilla L, Kacie K, Richard S, Edwin 

R, et al. Oxygenation based perfusion assessment of diabetic foot 

ulcers using a breath-hold paradigm. ProcSPIE. 

2019;10873:1087304. DOI:10.1117/12.2509917 

233.Ramaprabha P, Ramani CP, Kesavan R. Study on microbiome 

of chronic non healing diabetic ulcers with special reference to 

biofilm and multidrug resistant strains. J Clin Diagn Res. 2021. 

DOI:10.7860/JCDR/2021/50126.15471  

https://doi.org/10.33137/cpoj.v7i2.43715


 

26 

Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

234.Strauss C, Anker A, Klein S, Kemper R, Brebant V, Prantl L, et 

al. Monitoring free flaps and replanted digits via perfusion index - A 

proof of concept study. Clin Hemorheol Microcirc. 2022;80(4):363-

71. DOI:10.3233/ch-211295  

235.Van Den Hoven P, Van Den Berg SD, Van Der Valk JP, Van 

Der Krogt H, Van Doorn LP, Van De Bogt KEA, et al. Assessment 

of tissue viability following amputation surgery using near-infrared 

fluorescence imaging with indocyanine green. Ann Vasc Surg. 

2022;78:281-7. DOI:10.1016/j.avsg.2021.04.030  

236.Zubair M, Ahmad J. Transcutaneous oxygen pressure 

(TcPO(2)) and ulcer outcome in diabetic patients: Is there any 

correlation? Diabetes Metab Syndr. 2019;13(2):953-8. 

DOI:10.1016/j.dsx.2018.12.008  

237.Chen CY, Wu RW, Hsu MC, Hsieh CJ, Chou MC. Adjunctive 

hyperbaric oxygen therapy for healing of chronic diabetic foot 

ulcers: A randomized controlled trial. J Wound Ostomy Continence 

Nurs. 2017;44(6):536-45. DOI:10.1097/won.0000000000000374  

238.Izadi M, Kheirjou R, Mohammadpour R, Aliyoldashi MH, 

Moghadam SJ, Khorvash F, et al. Efficacy of comprehensive ozone 

therapy in diabetic foot ulcer healing. Diabetes Metab Syndr. 

2019;13(1):822-5. DOI:10.1016/j.dsx.2018.11.060  

239.Oley MH, Oley MC, Noersasongko AD, Hatta M, Philips GG, 

Agustine, et al. Effects of hyperbaric oxygen therapy on vascular 

endothelial growth factor protein and mRNA in crush injury patients: 

A randomized controlled trial study. Int J Surg Open. 2021;29:33-9. 

DOI:10.1016/j.ijso.2021.01.003  

240.Oley MH, Oley MC, Tjandra DE, Sedu SW, Sumarauw ERN, 

Aling DMR, et al. Hyperbaric oxygen therapy in the healing process 

of foot ulcers in diabetic type 2 patients marked by interleukin 6, 

vascular endothelial growth factor, and PEDIS score: A randomized 

controlled trial study. Int J Surg Open. 2020;27:154-61. 

DOI:10.1016/j.ijso.2020.11.012  

241.Viswanathan V, Juttada U, Babu M. Efficacy of recombinant 

human epidermal growth factor (Regen-D 150) in healing diabetic 

foot ulcers: A hospital-based randomized controlled trial. Int J Low 

Extrem Wounds. 2020;19(2):158-64. DOI:10.1177/ 

1534734619892791  

242.Chiang N, Rodda OA, Sleigh J, Vasudevan T. Effects of topical 

negative pressure therapy on tissue oxygenation and wound 

healing in vascular foot wounds. J Vasc Surg. 2017;66(2):564-71. 

DOI:10.1016/j.jvs.2017.02.050  

243.Nolan GS, Smith OJ, Heavey S, Jell G, Mosahebi A. 

Histological analysis of fat grafting with platelet-rich plasma for 

diabetic foot ulcers-A randomised controlled trial. Int Wound J. 

2022;19(2):389-98. DOI:10.1111/iwj.13640  

244.Nur Rosyid F, Dharmana E, Suwondo A, Hs K, Sugiarto S. The 

effect of bitter melon (Momordica Charantia L.) leaves extract on 

TNF-α serum levels and diabetic foot ulcers improvement: 

Randomized controlled trial. Biomed Pharmacol J. 2018;11:1413-

21. DOI:10.13005/bpj/1505  

245.Chen J, Bao X, Meng T, Sun J, Yang X. Zeolitic imidazolate 

framework-67 accelerates infected diabetic chronic wound healing. 

Chem Eng J. 2022;430:133091. DOI:10.1016/j.cej.2021.133091  

246.Chen Z, Haus JM, DiPietro LA, Koh TJ, Minshall RD. 

Neutralization of excessive CCL28 improves wound healing in 

diabetic mice. Front Pharmacol. 2023;14:1087924. 

DOI:10.3389/fphar.2023.1087924  

247.Derakhshandeh H, Aghabaglou F, McCarthy A, Mostafavi A, 

Wiseman C, Bonick Z, et al. A wirelessly controlled smart bandage 

with 3d-printed miniaturized needle arrays. Adv Funct Mater. 

2020;30(13). DOI:10.1002/adfm.201905544  

248.Gao S, Chen T, Wang Z, Ji P, Xu L, Cui W, et al. Immuno-

activated mesenchymal stem cell living electrospun nanofibers for 

promoting diabetic wound repair. J Nanobiotechnology. 

2022;20(1):294. DOI:10.1186/s12951-022-01503-9  

249.Greene CJ, Anderson S, Barthels D, Howlader MSI, Kanji S, 

Sarkar J, et al. DPSC products accelerate wound healing in diabetic 

mice through induction of SMAD molecules. Cells. 2022;11(15). 

DOI:10.3390/cells11152409  

250.Hassan RF, Kadhim HM. Comparative effects of phenolic 

extract as an ointment dosage form in inducing wound healing in 

mice and β-sitosterol in experimentally induced acute wound 

healing in mice. J Pharm Negat Results. 2022;13(3):194-203. 

DOI:10.47750/pnr.2022.13.03.031  

251.Jing S, Li H, Xu H. Mesenchymal stem cell derived exosomes 

therapy in diabetic wound repair. Int J Nanomedicine. 

2023;18:2707-20. DOI:10.2147/ijn.S411562  

252.Kanji S, Das M, Joseph M, Aggarwal R, Sharma SM, Ostrowski 

M, et al. Nanofiber-expanded human CD34(+) cells heal cutaneous 

wounds in streptozotocin-induced diabetic mice. Sci Rep. 

2019;9(1):8415. DOI:10.1038/s41598-019-44932-7  

253.Khan MS, Tauqeer Ahmed M. Novel candidates for chronic 

diabetic wound healing. J Pak Assoc Dermatol. 2022;32(3):526-31.  

254.Li X, Xie X, Lian W, Shi R, Han S, Zhang H, et al. Exosomes 

from adipose-derived stem cells overexpressing Nrf2 accelerate 

cutaneous wound healing by promoting vascularization in a diabetic 

foot ulcer rat model. Exp Mol Med. 2018;50(4):1-14. 

DOI:10.1038/s12276-018-0058-5  

255.Liu C, Teo MHY, Pek SLT, Wu X, Leong ML, Tay HM, et al. A 

multifunctional role of leucine-rich α-2-glycoprotein 1 in cutaneous 

wound healing under normal and diabetic conditions. Diabetes. 

2020;69(11):2467-80. DOI:10.2337/db20-0585  

256.Paul TS, Das BB, Talekar YP, Banerjee S. Exploration of the 

role of a lithophytic fern, Pteris vittata L. in wound tissue 

regeneration and remodelling of genes in hyperglycaemic rat 

model. Clinical Phytoscience. 2020;6(1):79. DOI:10.1186/s40816-

020-00223-7  

257.Tellechea A, Bai S, Dangwal S, Theocharidis G, Nagai M, 

Koerner S, et al. Topical application of a mast cell stabilizer 

improves impaired diabetic wound healing. J Invest Dermatol. 

2020;140(4):901-11.e11. DOI:10.1016/j.jid.2019.08.449  

258.Tkaczyk C, Jones-Nelson O, Shi YY, Tabor DE, Cheng L, 

Zhang T, et al. Neutralizing staphylococcus aureus virulence with 

AZD6389, a three mab combination, accelerates closure of a 

diabetic polymicrobial wound. mSphere. 2022;7(3):e0013022. 

DOI:10.1128/msphere.00130-22  

259.Wang T, Zheng Y, Shi Y, Zhao L. pH-responsive calcium 

alginate hydrogel laden with protamine nanoparticles and 

hyaluronan oligosaccharide promotes diabetic wound healing by 

https://doi.org/10.33137/cpoj.v7i2.43715


 

27 

Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

enhancing angiogenesis and antibacterial activity. Drug Deliv 

Transl Res. 2019;9(1):227-39. DOI:10.1007/s13346-018-00609-8  

260.Xia G, Liu Y, Tian M, Gao P, Bao Z, Bai X, et al. 

Nanoparticles/thermosensitive hydrogel reinforced with chitin 

whiskers as a wound dressing for treating chronic wounds. J Mater 

Chem B. 2017;5(17):3172-85. DOI:10.1039/c7tb00479f  

261.Yadav S, Arya DK, Pandey P, Anand S, Gautam AK, Ranjan 

S, et al. ECM mimicking biodegradable nanofibrous scaffold 

enriched with Curcumin/ZnO to accelerate diabetic wound healing 

via multifunctional bioactivity. Int J Nanomedicine. 2022;17:6843-

59. DOI:10.2147/ijn.S388264  

262.Ye J, Kang Y, Sun X, Ni P, Wu M, Lu S. MicroRNA-155 

inhibition promoted wound healing in diabetic rats. Int J Low Extrem 

Wounds. 2017;16(2):74-84. DOI:10.1177/1534734617706636  

263.Zahid AA, Ahmed R, Ur Rehman SR, Augustine R, Hasan A. 

Reactive nitrogen species releasing hydrogel for enhanced wound 

healing. Annu Int Conf IEEE Eng Med Biol Soc. 2019;2019:3939-

42. DOI:10.1109/embc.2019.8856469  

264.Di Cristo F, Valentino A, De Luca I, Peluso G, Bonadies I, Di 

Salle A, et al. Polylactic acid/poly(vinylpyrrolidone) co-electrospun 

fibrous membrane as a tunable quercetin delivery platform for 

diabetic wounds. Pharmaceutics. 2023;15(3). 

DOI:10.3390/pharmaceutics15030805  

265.Kim JH, Ruegger PR, Lebig EG, VanSchalkwyk S, Jeske DR, 

Hsiao A, et al. High levels of oxidative stress create a 

microenvironment that significantly decreases the diversity of the 

microbiota in diabetic chronic wounds and promotes biofilm 

formation. Front Cell Infect Microbiol. 2020;10:259. 

DOI:10.3389/fcimb.2020.00259  

266.Nguyen TT, Jones JI, Wolter WR, Pérez RL, Schroeder VA, 

Champion MM, et al. Hyperbaric oxygen therapy accelerates 

wound healing in diabetic mice by decreasing active matrix 

metalloproteinase-9. Wound Repair Regen. 2020;28(2):194-201. 

DOI:10.1111/wrr.12782  

267.Shang W, Chen G, Li Y, Zhuo Y, Wang Y, Fang Z, et al. Static 

magnetic field accelerates diabetic wound healing by facilitating 

resolution of inflammation. J Diabetes Res. 2019;2019:5641271. 

DOI:10.1155/2019/5641271  

268.Ojalvo AG, Acosta JB, Marí YM, Mayola MF, Pérez CV, 

Gutiérrez WS, et al. Healing enhancement of diabetic wounds by 

locally infiltrated epidermal growth factor is associated with 

systemic oxidative stress reduction. Int Wound J. 2017;14(1):214-

25. DOI:10.1111/iwj.12592  

269.Al-Shibly I, Alhamdany M, Al-Kaif R, Al-Kaif L. Immunological 

base behind the increased susceptibility of diabetic patients for 

infections. Indian J Public Health Res Dev. 2019;10:3047. 

DOI:10.5958/0976-5506.2019.03343.6  

270.Camacho-Rodríguez H, Guillen-Pérez IA, Roca-Campaña J, 

Baldomero-Hernández JE, Tuero-Iglesias Á D, Galván-Cabrera JA, 

et al. Heberprot-P's effect on gene expression in healing diabetic 

foot ulcers. Medicc Rev. 2018;20(3):10-4. 

DOI:10.37757/mr2018.V20.N3.4  

271.García-Ojalvo A, Berlanga Acosta J, Figueroa-Martínez A, 

Béquet-Romero M, Mendoza-Marí Y, Fernández-Mayola M, et al. 

Systemic translation of locally infiltrated epidermal growth factor in 

diabetic lower extremity wounds. Int Wound J. 2019;16(6):1294-

303. DOI:10.1111/iwj.13189  

272.Naderi N, Zaefizadeh M. Expression of growth factors in re-

epithelialization of diabetic foot ulcers after treatment with non-

thermal plasma radiation. Biomedical Research (India). 

2017;28:3402-7.  

273.Pu D, Lei X, Leng W, Zheng Y, Chen L, Liang Z, et al. Lower 

limb arterial intervention or autologous platelet-rich gel treatment of 

diabetic lower extremity arterial disease patients with foot ulcers. 

Ann Transl Med. 2019;7(18):485. DOI:10.21037/atm.2019.07.87  

274.Baumfeld D, Baumfeld T, Macedo B, Zambelli R, Lopes F, Nery 

C. Factors related to amputation level and wound healing in diabetic 

patients. Acta Ortop Bras. 2018;26(5):342-5. DOI:10.1590/1413-

785220182605173445  

275.Kapukaya R, Kapukaya A, Keklikcioglu B, Özdemir AA. How 

important are mean platelet volume and neutrophil values in 

diabetic foot amputation decision? Eur J Plast Surg. 

2021;44(4):507-10. DOI:10.1007/s00238-020-01773-2  

276.Morisaki K, Yamaoka T, Iwasa K. Risk factors for wound 

complications and 30-day mortality after major lower limb 

amputations in patients with peripheral arterial disease. Vascular. 

2018;26(1):12-7. DOI:10.1177/1708538117714197  

277.Trejo J, Ryan E, Khan F, Iannuzzi N, Chansky H, Lack WD. 

Risk factors for failure of limb salvage among veterans with foot 

ulcers. Foot Ankle Surg. 2022;28(5):584-7. 

DOI:10.1016/j.fas.2021.06.003  

278.Wu T, Xie D, Zhao X, Xu M, Luo L, Deng D, et al. Enhanced 

expression of miR-34c in peripheral plasma associated with 

diabetic foot ulcer in type 2 diabetes patients. Diabetes Metab 

Syndr Obes. 2021;14:4263-73. DOI:10.2147/dmso.S326066  

279.Yang AE, Hartranft CA, Reiss A, Holden CR. Improving 

outcomes for lower extremity amputations using intraoperative 

fluorescent angiography to predict flap viability. Vasc Endovascular 

Surg. 2018;52(1):16-21. DOI:10.1177/1538574417740048  

280.JBI levels of evidence [Internet]. Joanna Briggs Institute.  

2013; [cited 2024, July 5]. Available from: 

https://jbi.global/sites/default/files/2019-05/JBI-Levels-of-

evidence_2014_0.pdf 

281.Metcalf D, Haalboom M, Bowler P, Gamerith C, Sigl E, 

Hasmann Heinzle A, et al. Elevated wound fluid pH correlates with 

increased risk of wound infection. Wound Medicine. 

2019;26:100166. DOI:10.1016/j.wndm.2019.100166  

282.Shah P, Inturi R, Anne D, Jadhav D, Viswambharan V, 

Khadilkar R, et al. Wagner's classification as a tool for treating 

diabetic foot ulcers: Our observations at a suburban teaching 

hospital. Cureus. 2022;14(1):e21501. DOI:10.7759/cureus.21501  

283.How many studies should be included in a systematic review? 

[internet]. DistillerSR Inc. [cited 2024, July 5]. Available from: 

https://www.distillersr.com/resources/systematic-literature-

reviews/how-many-studies-should-be-included-in-a-systematic-

review 

284.Development WOfEC-oa. Low- and middle-income countries 

Internet: Wellcome; 2024 [Available from: 

https://doi.org/10.33137/cpoj.v7i2.43715
https://jbi.global/sites/default/files/2019-05/JBI-Levels-of-evidence_2014_0.pdf
https://jbi.global/sites/default/files/2019-05/JBI-Levels-of-evidence_2014_0.pdf
https://www.distillersr.com/resources/systematic-literature-reviews/how-many-studies-should-be-included-in-a-systematic-review
https://www.distillersr.com/resources/systematic-literature-reviews/how-many-studies-should-be-included-in-a-systematic-review
https://www.distillersr.com/resources/systematic-literature-reviews/how-many-studies-should-be-included-in-a-systematic-review


 

28 

Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

https://wellcome.org/grant-funding/guidance/prepare-to-apply/low-

and-middle-income-countries 

285.Yao B. International research collaboration: Challenges and 

opportunities. J Diagn Med Sonogr. 2021;37(2):107-8. 

DOI:10.1177/8756479320976130  

286.Franzen SR, Chandler C, Lang T. Health research capacity 

development in low and middle income countries: Reality or 

rhetoric? A systematic meta-narrative review of the qualitative 

literature. BMJ Open. 2017;7(1):e012332. DOI:10.1136/bmjopen-

2016-012332  

287.Sen CK. Human wounds and its burden: An updated 

compendium of estimates. Adv Wound Care (New Rochelle). 

2019;8(2):39-48. DOI:10.1089/wound.2019.0946  

288.Guest JF, Fuller GW, Vowden P. Cohort study evaluating the 

burden of wounds to the UK's National Health Service in 

2017/2018: update from 2012/2013. BMJ Open. 

2020;10(12):e045253. DOI:10.1136/bmjopen-2020-045253  

289.Tricco AC, Lillie E, Zarin W, O'Brien K, Colquhoun H, Kastner 

M, et al. A scoping review on the conduct and reporting of scoping 

reviews. BMC Med Res Methodol. 2016;16:15. 

DOI:10.1186/s12874-016-0116-4  

290.Tod D, Booth A, Smith B. Critical appraisal. Int Rev Sport Exerc 

Psychol. 2022;15(1):52-72. DOI:10.1080/1750984X.2021.1952471  

291.Speich B, von Niederhäusern B, Schur N, Hemkens LG, Fürst 

T, Bhatnagar N, et al. Systematic review on costs and resource use 

of randomized clinical trials shows a lack of transparent and 

comprehensive data. J Clin Epidemiol. 2018;96:1-11. 

DOI:10.1016/j.jclinepi.2017.12.018  

292.Morris ZS, Wooding S, Grant J. The answer is 17 years, what 

is the question: Understanding time lags in translational research. 

J R Soc Med. 2011;104(12):510-20. DOI:10.1258/jrsm.2011. 

110180  

293. Wound management clinical practice guidelines tissue viability 

service [Internet]. East London. 2019; [cited 2024, July 5]. Available 

from:https://www.elft.nhs.uk/sites/default/files/Wound%20Manage

ment%20Guidelines%206.0.pdf 

294.Bryant JL, Brooks TL, Schmidt B, Mostow EN. Reliability of 

wound measuring techniques in an outpatient wound center. 

Ostomy Wound Manage. 2001;47(4):44-51. 

295.Keast DH, Bowering CK, Evans AW, Mackean GL, Burrows C, 

D'Souza L. Measure: A proposed assessment framework for 

developing best practice recommendations for wound assessment. 

Wound Repair Regen. 2004;12(3 Suppl):S1-17. 

DOI:10.1111/j.1067-1927.2004.0123S1.x  

296.Shah A, Wollak C, Shah JB. Wound measurement techniques: 

Comparing the use of ruler method, 2D imaging and 3D scanner. J 

Am Coll Clin Wound Spec. 2013;5(3):52-7. 

DOI:10.1016/j.jccw.2015.02.001  

297.Khalid KA, Nawi AFM, Zulkifli N, Barkat MA, Hadi H. Aging and 

wound healing of the skin: A review of clinical and 

pathophysiological hallmarks. Life (Basel). 2022;12(12). 

DOI:10.3390/life12122142  

298.Engeland CG, Sabzehei B, Marucha PT. Sex hormones and 

mucosal wound healing. Brain Behav Immun. 2009;23(5):629-35. 

DOI:10.1016/j.bbi.2008.12.001  

299.Jung MK, Callaci JJ, Lauing KL, Otis JS, Radek KA, Jones MK, 

et al. Alcohol exposure and mechanisms of tissue injury and repair. 

Alcohol Clin Exp Res. 2011;35(3):392-9. DOI:10.1111/j.1530-

0277.2010.01356.x  

300.McDaniel JC, Browning KK. Smoking, chronic wound healing, 

and implications for evidence-based practice. J Wound Ostomy 

Continence Nurs. 2014;41(5):415-23; quiz E1-2. 

DOI:10.1097/won.0000000000000057  

301.Stechmiller JK. Understanding the role of nutrition and wound 

healing. Nutr Clin Pract. 2010;25(1):61-8. 

DOI:10.1177/0884533609358997  

302.Robson MC. Wound infection. A failure of wound healing 

caused by an imbalance of bacteria. Surg Clin North Am. 

1997;77(3):637-50. DOI:10.1016/s0039-6109(05)70572-7  

303.Rodriguez PG, Felix FN, Woodley DT, Shim EK. The role of 

oxygen in wound healing: A review of the literature. Dermatol Surg. 

2008;34(9):1159-69. DOI:10.1111/j.1524-4725.2008.34254.x  

304.Raffetto JD, Ligi D, Maniscalco R, Khalil RA, Mannello F. Why 

venous leg ulcers have difficulty healing: Overview on 

pathophysiology, clinical consequences, and treatment. J Clin Med. 

2020;10(1). DOI:10.3390/jcm10010029  

305.Yepson H, Mazzone B, Eskridge S, Shannon K, Awodele E, 

Farrokhi S, et al. The influence of tobacco use, alcohol 

consumption, and weight gain on development of secondary 

musculoskeletal injury after lower limb amputation. Arch Phys Med 

Rehabil. 2020;101(10):1704-10. DOI:10.1016/j.apmr.2020.04.022  

306.Lind J, Kramhøft M, Bødtker S. The influence of smoking on 

complications after primary amputations of the lower extremity. Clin 

Orthop Relat Res. 1991(267):211-7.  

307.Nishio Y, Tsuji Y, Kitano I, Terashi H. Influence of peripheral 

arterial disease on wound healing in heel pressure ulcers. Kobe J 

Med Sci. 2022;67(4):E146-e54.  

308.Churilov I, Churilov L, Murphy D. Do rigid dressings reduce the 

time from amputation to prosthetic fitting? A systematic review and 

meta-analysis. Ann Vasc Surg. 2014;28(7):1801-8. 

DOI:10.1016/j.avsg.2014.05.002  

309.Mathew-Steiner SS, Roy S, Sen CK. Collagen in wound 

healing. Bioengineering (Basel). 2021;8(5). 

DOI:10.3390/bioengineering8050063  

310.Cattano NM, Driban JB, Cameron KL, Sitler MR. Impact of 

physical activity and mechanical loading on biomarkers typically 

used in osteoarthritis assessment: current concepts and knowledge 

gaps. Ther Adv Musculoskelet Dis. 2017;9(1):11-21. 

DOI:10.1177/1759720x16670613  

311.Boyko EJ, Zelnick LR, Braffett BH, Pop-Busui R, Cowie CC, 

Lorenzi GM, et al. Risk of foot ulcer and lower-extremity amputation 

among participants in the diabetes control and complications 

trial/epidemiology of diabetes interventions and complications 

study. Diabetes Care. 2022;45(2):357-64. DOI:10.2337/dc21-1816  

https://doi.org/10.33137/cpoj.v7i2.43715
https://wellcome.org/grant-funding/guidance/prepare-to-apply/low-and-middle-income-countries
https://wellcome.org/grant-funding/guidance/prepare-to-apply/low-and-middle-income-countries
https://www.elft.nhs.uk/sites/default/files/Wound%20Management%20Guidelines%206.0.pdf
https://www.elft.nhs.uk/sites/default/files/Wound%20Management%20Guidelines%206.0.pdf


 

29 

Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

312.De Silva GS, Saffaf K, Sanchez LA, Zayed MA. Amputation 

stump perfusion is predictive of post-operative necrotic eschar 

formation. Am J Surg. 2018;216(3):540-6. DOI:10.1016/ 

j.amjsurg.2018.05.007  

313.Yin V, Cobb JP, Wightman SC, Atay SM, Harano T, Kim AW. 

Centers for disease control (CDC) wound classification is 

prognostic of 30-day readmission following surgery. World J Surg. 

2023;47(10):2392-400. DOI:10.1007/s00268-023-07093-3  

314.Do HTT, Edwards H, Finlayson K. Surgical wound assessment 

tool: Construct validity and inter-rater reliability of a tool designed 

for nurses. J Clin Nurs. 2023;32(1-2):83-95. 

DOI:10.1111/jocn.16476  

315.Firth K, Smith K, Sakallaris BR, Bellanti DM, Crawford C, Avant 

KC. Healing, a concept analysis. Glob Adv Health Med. 

2015;4(6):44-50. DOI:10.7453/gahmj.2015.056  

316.Doering LV, Moser DK, Lemankiewicz W, Luper C, Khan S. 

Depression, healing, and recovery from coronary artery bypass 

surgery. Am J Crit Care. 2005;14(4):316-24.  

317.Sahu A, Sagar R, Sarkar S, Sagar S. Psychological effects of 

amputation: A review of studies from India. Ind Psychiatry J. 

2016;25(1):4-10. DOI:10.4103/0972-6748.196041  

318.Peters CML, de Vries J, Steunenberg SL, Ho GH, Lodder P, 

van der Laan L. Is There an important role for anxiety and 

depression in the elderly patients with critical limb ischemia, 

especially after major amputation? Ann Vasc Surg. 2019;58:142-

50. DOI:10.1016/j.avsg.2018.10.045  

319.McElligott D. Healing: the journey from concept to nursing 

practice. J Holist Nurs. 2010;28(4):251-9. DOI:10.1177/ 

0898010110376321  

320.Levin J. What is "Healing"?: Reflections on diagnostic criteria, 

nosology, and etiology. Explore (NY). 2017;13(4):244-56. 

DOI:10.1016/j.explore.2017.04.005  

321.Smith DG, McFarland LV, Sangeorzan BJ, Reiber GE, 

Czerniecki JM. Postoperative dressing and management strategies 

for transtibial amputations: A critical review. J Rehabil Res Dev. 

2003;40(3):213-24.  

322.Song Y, Jo Y, Sohn J, Kim R. A pilot study to explore a 

correlation between inflammatory markers and the wound healing 

rate in diabetic patients. Medicina (Kaunas). 2022;58(3). 

DOI:10.3390/medicina58030390  

323.Arsenault KA, Al-Otaibi A, Devereaux PJ, Thorlund K, Tittley 

JG, Whitlock RP. The use of transcutaneous oximetry to predict 

healing complications of lower limb amputations: A systematic 

review and meta-analysis. Eur J Vasc Endovasc Surg. 

2012;43(3):329-36. DOI:10.1016/j.ejvs.2011.12.004  

324.Matsumoto M, Nakagami G, Kitamura A, Kurita M, Suga H, 

Miyake T, et al. Ultrasound assessment of deep tissue on the 

wound bed and periwound skin: A classification system using 

ultrasound images. J Tissue Viability. 2021;30(1):28-35. 

DOI:10.1016/j.jtv.2020.08.002  

325.Patel S, Ershad F, Zhao M, Isseroff RR, Duan B, Zhou Y, et al. 

Wearable electronics for skin wound monitoring and healing. Soft 

Sci. 2022;2. DOI:10.20517/ss.2022.13  

326.Hawamdeh ZM, Othman YS, Ibrahim AI. Assessment of 

anxiety and depression after lower limb amputation in Jordanian 

patients. Neuropsychiatr Dis Treat. 2008;4(3):627-33. 

DOI:10.2147/ndt.s2541  

327.Singh R, Ripley D, Pentland B, Todd I, Hunter J, Hutton L, et 

al. Depression and anxiety symptoms after lower limb amputation: 

the rise and fall. Clin Rehabil. 2009;23(3):281-6. 

DOI:10.1177/0269215508094710  

328.Nikolajsen L, Ilkjaer S, Krøner K, Christensen JH, Jensen TS. 

The influence of preamputation pain on postamputation stump and 

phantom pain. Pain. 1997;72(3):393-405. DOI:10.1016/s0304-

3959(97)00061-4  

329.PLUS-M [Internet]. University of Washington. 2013; [cited 

2024, July 5]. Available from: https://plus-m.org/ 

330.Ambler GK, Brookes-Howell L, Jones JAR, Verma N, 

Bosanquet DC, Thomas-Jones E, et al. Development of core 

outcome sets for people undergoing major lower limb amputation 

for complications of peripheral vascular disease. Eur J Vasc 

Endovasc Surg. 2020;60(5):730-8. DOI:10.1016/j.ejvs.2020.06. 

021  

331.Gethin G, Ivory JD, Sezgin D, Muller H, O'Connor G, Vellinga 

A. What is the "normal" wound bed temperature? A scoping review 

and new hypothesis. Wound Repair Regen. 2021;29(5):843-7. 

DOI:10.1111/wrr.12930  

332.Derwin R, Patton D, Strapp H, Moore Z. Wound pH and 

temperature as predictors of healing: An observational study. J 

Wound Care. 2023;32(5):302-10. DOI:10.12968/jowc.2023.32. 

5.302  

333.Holzer-Geissler JCJ, Schwingenschuh S, Zacharias M, 

Einsiedler J, Kainz S, Reisenegger P, et al. The impact of prolonged 

inflammation on wound healing. Biomedicines. 2022;10(4). 

DOI:10.3390/biomedicines10040856  

334.Vaisson G, Provencher T, Dugas M, Trottier M, Chipenda 

Dansokho S, Colquhoun H, et al. User involvement in the design 

and development of patient decision aids and other personal health 

tools: A systematic review. Med Decis Making. 2021;41(3):261-74. 

DOI:10.1177/0272989x20984134  

335.Stoll CRT, Izadi S, Fowler S, Green P, Suls J, Colditz GA. The 

value of a second reviewer for study selection in systematic 

reviews. Res Synth Methods. 2019;10(4):539-45. DOI:10. 

1002/jrsm.1369  

336.Suri, H. Ethical considerations of conducting systematic 

reviews in educational research. In: Zawacki-Richter, O., Kerres, 

M., Bedenlier, S., Bond, M., Buntins, K. (eds) systematic reviews in 

educational research. Springer VS, Wiesbaden. 2020. (41-54). 

DOI:10.1007/978-3-658-27602-7_3 

337.Van Nes F, Abma T, Jonsson H, Deeg D. Language 

differences in qualitative research: Is meaning lost in translation? 

Eur J Ageing. 2010;7(4):313-6. DOI:10.1007/s10433-010-0168-y  

338.Paez A. Gray literature: An important resource in systematic 

reviews. J Evid Based Med. 2017;10(3):233-40. 

DOI:10.1111/jebm.12266  

339.Gazendam AM, Slawaska-Eng D, Nucci N, Bhatt O, Ghert M. 

The impact of industry funding on randomized controlled trials of 

https://doi.org/10.33137/cpoj.v7i2.43715
https://plus-m.org/


 

30 

Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

biologic therapies. Medicines (Basel). 2022;9(3). DOI:10.3390/ 

medicines9030018  

340.Lee L, Packer TL, Tang SH, Girdler S. Self-management 

education programs for age-related macular degeneration: A 

systematic review. Australas J Ageing. 2008;27(4):170-6. 

DOI:10.1111/j.1741-6612.2008.00298.x 

Abbreviations & Acronyms: 

Abbreviation 
& Acronym 

Definition 

CDC Centers for Disease Control  

CLTI Critical Limb Threatening Ischemia 

COMET 
Core Outcome Measures in Effectiveness 
Trials 

CRP C-Reactive Protein 

DEPA 
Depth of ulcer, Extent of bacterial 
colonization, Phase of ulcer, and Association 
etiology 

DFU Diabetic Foot Ulcer 

DTI Deep Tissue Injury 

DUSS Diabetic Ulcer Severity Score 

ECM Extracellular Matrix 

FDA Food & Drug Administration 

HIC High Income Country 

IV Intravenous 

JBI Joanna Briggs Institute 

LEAs Lower Extremity Amputation 

LMICs Low to Middle Income Countries 

mBJS Modified Bates-Jensen Score 

MMPs Matrix Metalloproteinases 

n Number 

NA Not Applicable 

NHS National Health Service 

NICE 
National Institute for Health and Care 
Excellence 

OHE Optimal Healing Framework 

OHP Hydroxyproline 

PEDIS 
Perfusion, Extent, Depth, Infection, and 
Sensation 

PLUS-M Prosthetic Limb Users Survey of Mobility 

PRISMA-ScR 
Preferred Reporting Items for Systematic 
Review and Meta-Analyses for Scoping 
Reviews 

PROs Patient Reported Outcomes 

RCTs Randomized Controlled Trials 

SINBAD 
Site, Ischemia, Neuropathy, Bacterial 
Infection, and Depth 

SSI Surgical Site Infection 

SWAT Surgical Wound Assessment Tool 

SWC Surgical Wound Classification 

TcPO2 Transcutaneous Oxygen Pressure 

TNP Topical Negative Pressure 

UK United Kingdom 

USA or US United States of America 

UT University of Texas 

VAS Visual Analogue Scale 

 

 

 

 

 

 

 

 

 

 

 

 

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Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

    Appendix 

 
APPENDIX A: 
Table A.1 (adapted from References 48 and 53): Data extraction tool used to extract data from all sources that passed both screening steps. NAST refers to data 
extraction categories that may not be applicable to all source types.  

 

Data to be Extracted Clarification of Data Extraction Category 
Scoping Review Details 

Scoping Review Title 
Wound Management, Healing, and Early Prosthetic Rehabilitation: Part 1 - A Scoping Review of Healing and Non-
Healing Definitions 

Review Objectives 
Summarized in Manuscript Section 1 (Introduction) 

Review Questions 

Evidence Source Details and Characteristics 

Citation Details Full Harvard APA 7th edition citation for the source including source URL. 

Study Type For example, an observational retrospective or case-controlled study.  

Country The geographical location where the source was generated.  

Setting For example, a hospital/medical Center, university, or research center.  

One Sentence Summary Summary of the study in one sentence.  

Details/Results Extracted from the Sources of Evidence 

Participant Characteristics For example, age range, gender, and comorbidities. Includes control group characteristics also.  

Sample Type and Size Refers to the number and type of participants investigated in the source (NAST). 

Wound Details This includes any details about the wound type, such as classification, average size, and burn or ulcer. 

Follow-up Time Refers to the time between or after reported outcome measures (NAST). 

Definition of Healing Definitions and terms are given for healthy (non-impaired) healing. 

Definition on Non-Healing Definitions and terms are given for unhealthy (impaired) healing.  

Chemical Biomarkers Discussed 
All chemical biomarkers discussed/measured in the source must be recorded here. See Manuscript Introduction 
for a definition of chemical.  

Physical Biomarkers Discussed 
All physical biomarkers discussed/measured in the source must be recorded here. See Manuscript Introduction 
for a definition of physical. 

Other Biomarkers Discussed All remaining biomarkers that do not fall into the chemical or physical category must be recorded here.  

Biomarker Measurement Techniques Summary of the discussed/used/described biomarker measurement techniques used in the source.  

Outcome Measures 
Reported outcome measures (aside from aforementioned biomarkers); for example, 3-year mortality may be the 
primary outcome measure.  

Significant Results Results of importance as judged by the reviewers.  

Limitations 
Key limitations of the biomarkers, biomarker quantification technologies, or methodologies that are explicitly 
mentioned in the source. 

Level of Evidence Level of evidence according to the JBI classification (Reference 280) (see Appendix C). 

Quality of Evidence Quality of evidence score generated using the QualSyst tool (Reference 61) (Appendix B). 

 
APPENDIX B: 
Table B.1 (Reference 61): QualSyst tool checklist for assessing the quality of quantitative studies. Note that NA is not an option for Criteria 1, 2, 4, 13 and 14. Each 
response is assigned a point score depending on how well it meets the criteria (“yes” = 2 points, “partial” = 1 points, and “no” = 0 points). Items not applicable to a 
certain study design are labelled as NA and excluded from the total score. A summary score is calculated by summing the total score and dividing by the possible 
score (the possible score is the maximum score (28 points) minus the number of “NA” responses multiplied by 2). 
 

Criteria Yes (2) Partial (1) No (0) NA 

1 Question/objective sufficiently described?     

2 Study design evident and appropriate?     

3 
Method of subject/comparison group selection or source of information/input variables 
described and appropriate? 

    

4 Subject (and comparison group, if applicable) characteristics sufficiently described?     

5 If interventional and random allocation was possible, was it described?     

6 If interventional and blinding of investigators was possible, was it reported?     

7 If interventional and blinding of subjects was possible, was it reported?     

8 
Outcome and (if applicable) exposure measure(s) well defined and robust to measurement / 
misclassification bias? Means of assessment reported? 

    

9 Sample size appropriate?     

10 Analytic methods described/justified and appropriate?     

11 Some estimate of variance is reported for the main results?     

12 Controlled for confounding?     

13 Results reported in sufficient detail?     

14 Conclusions supported by the results?     

 

Table B.2 (Reference 340): Ranking criteria for scores generated using the QualSyst quality assessment tool. The tool consists of a quantitative study checklist 
with 14 criteria. Each criterion can be scored 0, 1, or 2 points provided the study doesn’t, partially does, or does meet the criteria respectively. Thus, the greater 
the score the higher the quality of evidence. 
 

Study Type Maximum Possible Score 
Quality Threshold Scores 

Percentage (%) of Maximum Possible Score Quality 

Quantitative 28 

< 50% Limited 

≥ 50% and < 70% Adequate 

≥ 70% and < 80% Good 

≥ 80% Strong 

 

 

 

 

 

 

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32 

Williams-Reid H, Johannesson A, Buis A. Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing 
definitions. Canadian Prosthetics & Orthotics Journal. 2024; Volume 7, Issue 2, No.1. https://doi.org/10.33137/cpoj.v7i2.43715 

CANADIAN PROSTHETICS & ORTHOTICS JOURNAL 

ISSN: 2561-987X WOUND MANAGEMENT: HEALING AND NON-HEALING DEFINITIONS 

Williams-Reid et al., 2024 

APPENDIX C: 
Table C.1 (Reference 280): JBI levels of evidence for effectiveness. These levels are intended to be used alongside the supporting document outlining their use 

and using these levels does not preclude the need for careful reading, critical appraisal and clinical reasoning when applying evidence. 
 

Levels of Evidence - Effectiveness 

Level 1 – Experimental Designs 

Level 1.a – Systematic review of Randomized Controlled Trials (RCTs) 

Level 1.b – Systematic review of RCTs and other study designs 

Level 1.c – RCT 

Level 1.d – Pseudo-RCTs 

Level 2 – Quasi-Experimental Designs 

Level 2.a – Systematic review of quasi-experimental studies 

Level 2.b – Systematic review of quasi-experimental and other lower study designs 

Level 2.c – Quasi-experimental prospectively controlled study 

Level 2.d – Pre-test – post-test or historic/retrospective control group study 

Level 3 – Observational – Analytic 
Designs 

Level 3.a – Systematic review of comparable cohort studies 

Level 3.b – Systematic review of comparable cohort and other lower study designs 

Level 3.c – Cohort study with control group 

Level 3.d – Case-controlled study 

Level 3.e – Observational study without a control group 

Level 4 – Observational - Descriptive 
Studies 

Level 4.a – Systematic review of descriptive studies 

Level 4.b – Cross-sectional study 

Level 4.c – Case series 

Level 4.d – Case study 

Level 5 – Expert Opinion and Bench 
Research 

Level 5.a – Systematic review of expert opinion 

Level 5.b – Expert consensus 

Level 5.c – Bench research/single expert opinion 

 
Table C.2  

Levels of Evidence - Diagnosis 

Level 1 – Studies of Test 
Accuracy Among Consecutive 
patients 

Level 1.a – Systematic review of studies of test accuracy among consecutive patients 

Level 1.b – Study of test accuracy among consecutive patients 

Level 2 – Studies of Test 
Accuracy Among Non-
Consecutive Patients 

Level 2.a – Systematic review of studies of test accuracy among non-consecutive patients 

Level 2.b – Study of test accuracy among non-consecutive patients 

Level 3 – Diagnostic Case Control 
Studies 

Level 3.a – Systematic review of diagnostic case control studies 

Level 3.b – Diagnostic case-control study 

Level 4 – Diagnostic Yield Studies 
Level 4.a – Systematic review of diagnostic yield studies 

Level 4.b – Individual diagnostic yield study 

Level 5 – Expert Opinion and 
Bench Research 

Level 5.a – Systematic review of expert opinion 

Level 5.b – Expert consensus 

Level 5.c – Bench research/single expert opinion 

 
Table C.3  

Levels of Evidence - Prognosis 

Level 1 – Inception Cohort 
Studies 

Level 1.a – Systematic review of inception cohort studies 

Level 1.b – Inception cohort study 

Level 2 – Studies of All or None 
Level 2.a – Systematic review of all or none studies 

Level 2.b – All or none studies 

Level 3 – Cohort Studies 
Level 3.a – Systematic review of cohort studies (or control arm of RCT) 

Level 3.b – Cohort study (or control arm of RCT) 

Level 4 – Case Series/Case 
Controlled/ Historically Controlled 
Studies 

Level 4.a – Systematic review of Case series/Case Controlled/Historically Controlled studies 

Level 4.b – Individual Case series/Case Controlled/Historically Controlled study 

Level 5 – Expert Opinion and 
Bench Research 

Level 5.a – Systematic review of expert opinion 

Level 5.b – Expert consensus 

Level 5.c – Bench research/single expert opinion 

 
Table C.4  

Levels of Evidence – Economic Evaluations 

Level 1 Decision model with assumptions and variables informed by systematic review and tailored to fit the decision-making context. 

Level 2 Systematic review of economic evaluations conducted in a setting similar to the decision makers. 

Level 3 
Synthesis/review of economic evaluations undertaken in a setting similar to that in which the decision is to be made and which are of high 
quality (comprehensive and credible measurement of costs and health outcomes, sufficient time period covered, discounting, and sensitivity 
testing). 

Level 4 
Economic evaluation of high quality (comprehensive and credible measurement of costs and health outcomes, sufficient time period covered, 
discounting and sensitivity testing) and conducted in setting similar to the decision-making context. 

Level 5 
Synthesis/review of economic evaluations of moderate and/or poor quality (insufficient coverage of costs and health effects, no discounting, 
no sensitivity testing, time period covered insufficient). 

Level 6 Single economic evaluation of moderate or poor quality (see directly above level 5 description of studies). 

Level 7 Expert opinion on incremental cost effectives of intervention and comparator. 

 
Table C.5  

Levels of Evidence - Meaningfulness 

Level 1 Qualitative or mixed-methods systematic review 

Level 2 Qualitative or mixed-methods synthesis 

Level 3 Single qualitative study 

Level 4 Systematic review of expert opinion 

Level 5 Expert opinion 

 

 

A
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