Targeting Chronic Inflammation: Extracellular Matrix Therapies in Hard-to-Heal Wounds

The extracellular matrix (ECM), found in all mammalian tissues, provides a bioactive environment that controls cell behavior via special chemical and mechanical signals.¹ The ECM is essential for the normal development, functioning, and homeostasis of all human-derived cells. It actively participates in the regulation of multiple processes and cell activities, including growth factors, receptors, hydration, and local tissue pH.² A vital component of tissues and organs, the ECM provides a scaffold for tissue and organ morphogenesis, maintenance, and post-injury reconstruction. Multiple varying proteins such as collagen, elastin, fibronectin, and proteoglycans are present in the ECM. ECMs provide a platform for the interaction of cells such as fibroblasts, macrophages, and endothelial cells, all of which participate in modulating inflammation.

Delayed and hard-to-heal wounds increase morbidity and mortality for patients, potentially leading to limb- and life- threatening infections while burdening the health care system. Medicare cost projections for all wounds are upwards of $30 billion annually.³ Advancements in wound care products geared towards hard-to-heal wounds may lead to better tissue integrity and return to function. Mammalian and bioengineered ECMs have shown to be a viable potential solution² designed to mimic the natural ECM and provide the necessary support for cellular processes that are impaired in chronic wounds. By improving the structure and function of the ECM, these therapies may help support the healing process, contribute to reducing inflammation, and play a role in restoring normal tissue architecture.

A Closer Look at How ECMs Support Wound Healing

Chronic inflammation is a major contributing factor to delayed healing, and one that ECMs can address. Stalling in the inflammatory phase of healing is often driven by an imbalance between pro-inflammatory and anti-inflammatory signals, leading to prolonged inflammatory responses and the failure of wound progression.⁴ M1 macrophages are consistent with a pro-inflammatory environment and are elevated in these chronic and hard to heal wounds. When a wound is on a healing trajectory, the macrophage phenotype shift from M1 to M2, thus also shifting from a pro-inflammatory to an anti-inflammatory wound microenvironment.⁵ 

ECM-derived biomaterials, with an innate capacity to drive macrophages towards that pro-healing phenotype, can potentially aid in resolving inflammation and promoting tissue repair.⁶ In further mitigating the role of the pro-inflammatory response, ECMs can store and release cytokines and growth factors like TGF-β, VEGF, and IL-10, which help in resolving inflammation and encouraging the transition to the proliferative phase of wound healing.⁹

ECMs are also integral in the migration and proliferation of cells that are vitally important in the immunoregulation of wound healing. Disrupted ECMs interfere with this process. For instance, fibroblasts are essential for collagen deposition and tissue repair, as they migrate to a wound site and deposit collagen proteins. Applying ECMs works to support this migration, contributing to structural support and a framework to allow for healing.⁹ Additionally, ECMs aid keratinocytes by increasing their cellular migration, which allows for increased epithelialization with promotion of new native tissue.⁶

Proper wound bed vascularization is also critical in advancing chronic wounds to healing. ECM components play a key role in growth factor retention and signaling to promote this vascularity. ECM products maintain the architectural integrity similar to native ECM, allowing for recellularization and vascularization.¹⁰ The vascular basement membrane contains collagen and fibronectin, and ECM products have an abundance of these, allowing for increased support of new blood vessels.¹¹ Angiogenesis promotion by ECMs also includes endothelial cell migration, contributing to adequate oxygen and nutrient delivery to the wound site, often compromised in chronic wounds.¹¹

Bacterial load is another factor that contributes to a prolonged inflammatory response. A higher concentration of hyaluronic acid included within ECM products has been shown to reduce bacterial hyaluronidase activity, thus reducing bacterial proliferation and decreasing adhesions of bacteria within the wound site.¹² Furthermore, ECM contains laminin and fibronectin, which disrupt bacterial DNA.⁹

The remodeling phase of wound healing can also see an impact from a persistent pro-inflammatory and ischemic wound microenvironment via elevated production of matrix metalloproteinases (MMPs). MMP elevation increases ECM degradation.¹³ ECM deposition and collagen fiber reorganization are essential for tissue repair as it re-establishes the skin’s structural integrity and barrier function, including proper epithelial cell differentiation.¹⁴ Excessive MMP activity and ECM degradation instead inhibits re-epithelization, and results in the wound remaining open. Application of ECM-derived products can help to regulate the expression and activity of MMPs, ensuring that ECM degradation occurs in a controlled manner to avoid excessive tissue breakdown. This regulation helps reduce chronic inflammation by preventing the accumulation of degraded ECM fragments that could act as pro-inflammatory signals.⁹

Tissue remodeling is crucial in healing of wounds and the maintenance of that healing to provide a functional anatomical result. Application of ECM to a chronic wound introduces components such as collagen, elastin, and fibronectin, which can aid in remodeling.⁹ Collagen deposition from these products aids in the formation of native ECM, as well. Furthermore, the ECM components of products can support wound contraction, potentially decreasing the amount of scar tissue formation post-healing and increasing host tissue volume.⁹ Application of ECM provides a scaffold for this remodeling, helping to bridge innate healing components across a wound bed while increasing the amount of anti-inflammatory and pro-healing cell contact.⁹

Some ECM components can have direct effects on the immune system. Fibronectin can modulate the immune response by binding to specific receptors on immune cells, influencing leukocyte activity, and promoting tissue repair rather than chronic inflammation.² The ECM also plays a role in stem cell recruitment and differentiation. Recent evidence indicates the deregulation of stem cell differentiation plays a key role in diseases associated with tissue degeneration, including chronic wounds. By providing biochemical cues, the ECM can attract mesenchymal stem cells (MSCs) and influence their differentiation into various cell types.¹⁵ These stem cells can help replace damaged tissue and promote healing, reducing chronic inflammation.

Mammalian-derived ECMs have shown to be particular useful, supporting chronic wound healing while providing anatomical resemblance of native tissue.³ Decellularized ECM tissue products are an important alternative to native ECM for reconstructing cutaneous tissue deficits, since they maintain the complex protein structure and provide functional domains for cell differentiation while reducing the host immune response.⁴ Efficacy of the decellularization protocol used by manufacturers is a key determinant of the immunomodulatory capacity of a decellularized tissue-derived biomaterial. Remnants of foreign body antigens may contribute to the persistence of a pro-inflammatory, non-healing, M1 phenotype.⁷ In contrast, however, more intensive or thorough methods of decellularization can elicit a predominant M2 phenotype, as demonstrated in decellularized small intestine submucosa-derived biomaterials.⁸ Moreover, recent evidence supports that implanting decellularized tissue ECM-derived biomaterials can drive the foreign body response towards a modulatory phenotype.⁸ Clinicians should be aware of the processing of their desired product and inquire about the specific techniques used to yield said products. This can than better inform one’s clinical decision-making in patient care. 

In Summary

In chronic wounds, the ECM is central in both controlling inflammation and guiding tissue repair. As outline above, it helps regulate inflammatory responses, supports cellular migration and proliferation, facilitates tissue remodeling, and controls ECM degradation. By promoting a balanced inflammatory environment and supporting the proper healing cascade, ECMs are essential in mitigating the chronic inflammation that often underlies hard-to-heal wounds. ECM-based therapies can be a particularly effective option to restore these functions and potentially improve wound healing outcomes. By better understanding the role of ECMs at the cellular level, clinicians can better incorporate these concepts into their therapeutic choices. 

Dr. Miller is a fellowship-trained surgeon and co-owner of Sunshine Ankle and Foot Experts in Orlando, Florida. He is board certified by the American Board of Foot and Ankle Surgeons, specializing in reconstruction, trauma and limb salvage. He has lectured locally and nationally, and volunteers for multiple podiatric organizations. 
 
Dr. Miller discloses that he is a key opinion leader for Convatec.