ABSTRACT

Background: Wound healing complications could sometimes cause a transformation from acute to
chronic wound. Proteolytic enzymes have been used to facilitate tissue repair ever since ancient times.
Trypsin: Chymotrypsin, proteolytic enzyme oral preparation which has been in clinical use ever since
1960s, provides a better resolution of inflammatory symptoms and promotes speedier recovery of acute
tissue injury by minimizing the fibrinolytic shut down. Pathophysiology studies revealed that the
physiological process of wound healing may be disrupted by high levels of proteases and/ or an
imbalance between the protease and their inhibitors. It was suggested that measurement of the
systemic and local response to injury using serum inflammatory biomarkers as indicator, may allow
accelerated intervention for wound closure and treatment.

Objective: The main aim of the study was to explore the literature that refers to the role of proteases
especially chymoral as biomarkers in predicting wound healing progress. The secondary aim was to
establish the relevance of this knowledge to the morbidity experienced by our index patient and how it
might be useful for wound treatment.

Material and methods: A systematic literature review using the PubMed clinical queries, Cochrane
database, and Google scholar was conducted to identify relevant articles published in the last 10 years.
The search words were,“Proteolytic enzymes”, Chymoral, AND Wound healing”. The articles were
selected in accordance with preset criteria and were then critically evaluated. The search strategy was
limited to the following type of articles: clinical trial, meta-analysis, randomized control trial.

Results: We identified 7 eligible studies based on our inclusion criteria: 3 randomized control trials
(RCT) and 4 clinical trials. We didn’t find any Meta-analysis. After we performed the additional search for
prospective studies and case series based on study design, research methodology, interpretation of
results, and statistical analysis, 3 papers with relevant information about proteases’ role in wound
healing were found. Statistically significant reduction in post-operative edema, hematoma formation
and reduction in pain and incidence of suture site infection, better cosmetic appearance of the scar and
decline in need for secondary suturing was noted, however this was level III evidence and was highly
disputed by level I evidence. Conflicting results were seen as clinical trials substantiating their efficacy
are consistently been disputed.

Discussions: Chronic wounds with abnormally elevated protease levels not controlled by the
physiological mechanisms of the body, impairs healing. The findings in this field are controversial.

Conclusions: The conflicting results of this literature review from clinical trials and randomized control
trials are not entirely unexpected. A reliable means of measuring the clinical effect of these protease
enzymes remains to be developed and this seems to be the major obstacle to the acceptance of the
efficacy of the enzymes. Substantiating the clinical effect due to protease enzymes relies on observers’
subjective interpretation.
“The evidence supporting the existence of anti-inflammatory effect in man for such enzymes as trypsin,
chymotrypsin, and streptokinase….is still unsatisfactory…the burden of responsibility for proving this effect
remains upon those who advocate their use” Sherry & Fletcher, 1960.

Keywords: Chymoral forte, Chymotrypsin: trypsin, Proteases, wound healing.

CONCLUSION Normal wound healing is the result of balanced tissue degradation and synthesis.
Controlled degradation of extracellular matrix in damaged tissue and controlled formation of the new
tissue is essential for the healing processes. There is poor and contradictory evidence available in the
literature that refers to the role of proteases as biomarkers in predicting wound healing progress and
how this knowledge it is relevant of for clinical practice. Consequently, no firm recommendations for
how to use this inconsistent information in wound healing evaluation can be done. There is a need for
further studies in this area with quality methodology, adequate sample size and clear end points. We
can conclude that wound fluid, wound biopsy, or blood plasma MMP levels could reflect wound status
and can be used as a possible prognostic indicator. Understanding this area better and implementing
long-term program, with specific targets, will assist the development of evaluation and therapeutic
strategies. It is clear that proteases are essential in the healing process and an increasing knowledge on
their activity and role in altering the wound environment is of great clinical value for the development of
innovative solutions for cost-effective diagnostic tests.

Proteases and Delayed Wound Healing

Significance
Proteases and their inhibitors contribute to the balance between extracellular matrix (ECM)
degradation and deposition, creating an equilibrium that is essential for the timely and
coordinated healing of cutaneous wounds. However, when this balance is disrupted, wounds are
led into a state of chronicity characterized by abundant levels of proteases and decreased levels
of protease inhibitors.

Discussion of Findings and Relevant Literature

Background
The normal tissue response to injury and the resulting wound-healing process involves an orderly
sequence of important pathways that are orchestrated via the movement of specialized cells and
secretion of signaling molecules.1 The end point of normal wound healing is the reformation of
skin integrity through epithelialization and remodeling, resulting in the production of functional
scar tissue (Fig. 1). While acute wounds normally heal in a sequenced and timely manner,
characterized by four major phases (namely, hemostasis, inflammation, proliferation, and
remodeling), chronic wounds remain in one particular stage of healing (usually the inflammatory
phase), disrupting the normal balance between deposition and degradation of ECM components
(Fig. 2).1

Take-Home Messages
 Chronic wounds remain in one particular stage of healing (usually the inflammatory
phase), which disrupts the normal balance between deposition and degradation of ECM
components
 The degradation and remodeling of the ECM by proteases, particularly MMPs, is a key
element of tissue repair
 Molecular differences exist between acute and chronic wound microenvironments,
including differences in the levels of proteases, proinflammatory cytokines, growth
factors, and matrix components
 Prolonged exposure of the wound tissues to proinflammatory cytokines may act to
stimulate the production of MMPs, while inhibiting the synthesis of TIMPs
 Many pathogenic bacteria secrete a range of proteases, of the serine, cysteine, and
metallo type that acts as virulence factors
 Wound fluids provide researchers with a useful way of measuring various markers of
wound progression; however, deviations in wound care protocols and sampling
techniques contribute to variation in results