How Inflammation Delays and Disrupts Wound Healing

The Four Phases of Acute Wound Healing

Wound healing is a carefully orchestrated process that occurs in four overlapping stages:

1. Hemostasis – blood clotting to stop bleeding

2. Inflammation – immune cells clear debris and pathogens

3. Proliferation – new tissue and blood vessels form

4. Remodeling – wound strengthens and matures over time

In acute wounds, this sequence flows smoothly. But in chronic wounds, that process becomes disrupted—often getting stuck in the inflammation phase.

What Goes Wrong in Chronic Wounds?

When the normal healing process is interrupted—often due to a missing or incomplete hemostasis phase—the wound fails to initiate the rest of the cascade.

As a result, these ulcers become locked into a self-sustaining cycle of chronic inflammation, marked by heavy neutrophil infiltration, reactive oxygen species, and tissue-damaging enzymes. Healing can only resume once this prolonged inflammatory state is interrupted and the wound’s microenvironment is rebalanced. If this inflammatory cycle is not broken, the wound regresses and any previous healing progress may be lost.

The Role of Inflammation in Delayed Healing

One of the most defining characteristics of chronic wounds is prolonged, unregulated inflammation. In an attempt to repair the damage, the body continuously sends inflammatory cells to the site—yet without resolution, this persistent response ultimately causes more harm than healing.

However, in chronic wounds, this response becomes excessive and unregulated. Instead of aiding recovery, it damages healthy tissue, disrupts healing signals, and prolongs the inflammatory phase.

Ischemia-Reperfusion Injury and Microvascular Damage

One of the most overlooked drivers of chronic wound formation is repetitive ischemia-reperfusion injury—a process in which tissues are deprived of oxygen (ischemia), then suddenly reoxygenated. While this might sound restorative, the rapid shift triggers intense inflammation that damages surrounding tissue.

This mechanism is widely recognized in cardiovascular and inflammatory diseases, and research suggests it plays a major role in initiating chronic inflammation in tissue surrounding ulcers.

When oxygen-deprived tissue is suddenly flooded with blood, it sparks a cascade of pathological events:

• White blood cells accumulate within blood vessels

• These cells migrate into surrounding tissue, intensifying inflammation

• Cytokine levels spike, activating destructive enzymes

• Microvessels become fibrotic, reducing circulation long-term

  
  

This pattern—congestion, cytokine overload, and fibrosis—worsens microvascular health and restricts oxygen delivery, stalling the wound’s ability to progress through the healing phases.

Additional vascular stressors include:

• Impaired blood flow from ischemia and vessel stiffness

• Increased pressure, friction, and shear that damage cells

• Small vessel hypertension triggering local inflammation

  
  

These stressors may impair tissue health well before a wound becomes visible.

When one does form, bacterial counts surge and trigger immune cell recruitment. Fibrotic changes in the microcirculation—such as type VI collagen buildup and declining oxygen—further signal hypoxia.

If the wound skips the hemostasis phase, these combined effects can lock it into a self-sustaining inflammatory state from the outset, significantly complicating healing.

Importantly, the four primary types of chronic wounds—pressure ulcers, diabetic foot ulcers, arterial ulcers, and venous ulcers—all share ischemia-reperfusion injury as a common root cause. Managing this cycle is essential for restoring balance to the wound environment.

How Biofilms and Bacteria Perpetuate Inflammation

Nearly all chronic wounds contain bacteria—but some form biofilms, slimy protective barriers that shield microbes from the immune system and antibiotics. These biofilms:

• Suppress immune responses

• Fuel low-grade infection

• Sustain inflammation

• Prevent re-entry into the healing cycle

  
  

Traditional wound cultures may fail to detect biofilm-based infections, as these bacterial communities often don't grow under standard lab conditions. Clinically, biofilms are suspected when a wound fails to respond to antimicrobial treatment or debridement.

Effective management typically includes repeated debridement, advanced antimicrobial dressings, and strategies aimed at disrupting the biofilm matrix.

Cytokines, MMPs, and the Breakdown of Healing Signals

In chronic wounds, inflammatory cytokines like TNF-α and IL-1β are present at levels up to 100 times higher than in acute wounds. These cytokines:

• Trigger enzymes called matrix metalloproteinases (MMPs)

• Break down collagen, growth factors, and their receptors

• Decrease levels of protective TIMP (tissue inhibitors of MMPs)

  
  

This biochemical imbalance degrades the extracellular matrix and essential healing signals. Clinically, it often presents as wound stagnation, excessive drainage, or visible slough that persists despite standard care.

Fibrosis, Hypoxia, and the Pain Connection

Prolonged inflammation leads to:

• Collagen overproduction and fibrosis

• Declining tissue oxygen levels

• A shift toward anaerobic metabolism, which produces acids

  
  

These acids trigger nerve receptors, contributing to the chronic pain often associated with non-healing wounds. This helps explain why chronic wounds tend to be more painful and harder to manage than acute wounds.

Understanding and addressing the underlying hypoxia and fibrosis are critical steps in reducing pain and promoting healing.

The Role of Free Radicals and Oxidative Stress

As neutrophils and macrophages attack perceived threats, they produce reactive oxygen species (ROS)—unstable molecules that damage cells. Over time:

• ROS levels overwhelm antioxidant defenses

• Cell membranes, proteins, and DNA are damaged

• Senescent (non-dividing) fibroblasts accumulate

• Healing slows or halts entirely

  
  

In wounds with high iron deposits (like venous ulcers), ROS generation accelerates further, worsening tissue destruction.

Clinically, oxidative stress can present as tissue degradation, delayed epithelialization, or non-responsiveness to standard care. Targeted interventions—such as topical antioxidants, oxygen therapies, and iron chelation—can help reduce oxidative damage and support a more favorable healing environment.

Why the Chronic Wound Microenvironment Matters

Every chronic wound shares a common feature: a dysfunctional microenvironment. This environment—overwhelmed by inflammatory signals, destructive enzymes, oxidative stress, fibrosis, and biofilms—disrupts the body’s natural healing cascade and keeps wounds locked in a prolonged inflammatory phase.

At the root of this disruption are several interconnected mechanisms: ischemia-reperfusion injury, bacterial biofilms, cytokine imbalances, fibrosis, and oxidative damage. Together, they converge to create a hostile biological setting that sustains tissue breakdown and resists repair.

Breaking that cycle requires targeted intervention to reduce inflammation, restore oxygen balance, and create the conditions required for healing to resume.

Advanced Wound Care: Breaking the Cycle of Chronic Inflammation

To help chronic wounds restart the healing process, clinicians should focus on:

• Wound bed preparation (debridement and moisture balance)

• Reducing biofilm burden

• Managing inflammation through advanced dressings and therapies

• Improving oxygen delivery (e.g., through hyperbaric oxygen therapy for wound care centers)

• Correcting underlying causes, such as pressure, ischemia, or blood glucose levels

  
  

At Shared Health Services, we partner with hospitals and providers to deliver the tools, training, and clinical guidance needed to address these complex clinical and operational challenges. From customized wound care pathways and real-time clinical support to hyperbaric program development, clinical staff training, and seamless integration into existing care teams, we equip our partners to build effective, scalable, evidence-based wound care programs that align with today’s standards of advanced wound care delivery.

Whether you're launching a new clinic, strengthening an existing service line, reopening after disruption, or transitioning to a new delivery model, SHS works alongside your team to deliver a thoughtful, results-driven plan aligned with your operational goals. Our approach is tailored, collaborative, and designed to deliver long-term value—without adding unnecessary cost or complexity.

The result? Wound care programs that deliver clinical credibility, operational efficiency, and measurable improvement in healing outcomes—precisely what today’s healthcare leaders expect—and what your patients deserve.

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