Cellular and/or Tissue-Based Products: Helping to Close Chronic Wounds

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Introduction

Wound healing typically progresses through four phases: hemostasis, inflammation, cell proliferation or granulation and repair, and epithelialization and remodeling of scar tissue.1 Clinicians should achieve wound closure through a standardized framework such as the TIMERS (tissue management, infection or inflammation, moisture balance, edge or epithelialization, regeneration, and social factors) tool, which provides a comprehensive approach to wound management and optimizes the wound bed and conditions to support progression of wounds through the healing process.2

The Role of Chronic Inflammation in Wound Healing

When wounds fail to progress toward healing after an appropriate amount of time, the clinical approach to wound management should be reevaluated, and advanced modalities such as cellular and/or tissue-based products (CTPs) may be considered.3

Chronic and nonhealing wounds often stall in the inflammatory phases of healing. Biofilm is present in the majority of chronic wounds and is estimated to contribute to approximately 60% of chronic wound infections.4 The presence of bacteria and their endotoxins in the wound is related to increases in inflammatory cytokines and growth factors.5

A biofilm-related inflammatory response may contribute to persistent infection and impaired wound healing because such responses have been demonstrated to impair endothelial migration and the growth of granulation tissue.5 Biofilm targets many of the components that mediate the innate immune response to the wound microbiome, including:

  • Oxygen concentration
  • pH level
  • Blood platelets
  • Neutrophils
  • Macrophages

The components listed here all play an essential role in the inflammatory phase of healing. The release of the aforementioned excessive cytokines within the wound bed marks a prolonged inflammatory phase. The prolonged presence of neutrophils delays wound healing by releasing inflammatory factors, oxygen species, and proteinases that degrade the extracellular matrix and proteins required for healing. In addition, the process can damage healthy periwound tissue.5

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Proinflammatory macrophages and increased production of matrix metalloproteinases (MMPs) damage the wound extracellular matrix, thus creating an underlying pathologic process of chronic, nonhealing wounds. This process describes the stalled inflammation that can be observed in wounds with biofilm.5 When MMPs become imbalanced or overproduced, essential proteins are destroyed, inflammation is prolonged, and ischemia and biofilm can set into the wound. Potentially, the presence of biofilm or infection and the subsequent stalled healing degrade the condition of the wound.

Restoring Wound Healing Functionality

Optimization of the wound environment may be achieved through the use of a variety of methods to support regulation of MMPs in the wound bed, including using basic principles of good wound healing. Using a “step down, step up” approach helps address issues of wound infection and biofilm. This approach recommends a combination of interventions, such sharp debridement, which removes senescent cells and unhealthy tissues that contribute to the overproduction of MMPs. Topical antimicrobials and/or systemic antibiotics as well as advanced wound therapies may also be considered on evaluation of the wound’s progression.6

Using Dressings to Address MMPs

Some dressing products support the regulation of MMP expression. These dressings include those that contain superabsorbent polymers, which can bind MMPs to reduce their activity, as well as dressings with a high ionic charge. Furthermore, these dressings may also inhibit bacterial proteases.7

Biofilm Management: The Use of CTPs

CTPs may also support the restoration of normal healing functions.8 CTPs are available in a wide array of formats and compositions, including:

  • Viable or nonviable cells
  • Cultured and noncultured cells
  • Bioengineered cells
  • Human and animal sources

CTPs, in combination with biofilm-targeting strategies and the standard of care, can offer several benefits for wound healing, including protection from infection and injury. CTPs serve as a scaffold within the wound bed to provide transportation for regenerative cells and biomaterials to support the natural wound healing process.9

MMPs and Collagen

Providing MMPs with a sacrificial substrate, such as a collagen-based dressing or CTPs that contain collagen, may support optimization of the wound environment.10 MMPs can attack the donated collagen from the CTP instead of the healing modulators in the wound. CTPs that contain collagen and antimicrobial agent(s) may be helpful in lowering MMPs and encouraging wound closure, such as products that contain polyhexamethylene biguanide or silver, which can support bioburden control in the wound environment.11

Bioengineered CTPs

Studies involving a bioengineered living cell CTP demonstrated activation of keratinocytes at the wound edge, restoration of fibroblast functionality resulting in MMP balance and stabilization of the wound extracellular matrix, and regulation of growth factor signaling within the wound, among other benefits to support transforming a chronic wound into an acute wound.12-14 These improved factors resulted in high closure rates in a study population.

Conclusion

When wounds fail to progress through the normal cascade of healing, clinicians should consider the factors that may impede wound healing, such as infection and biofilm, and utilize a targeted, multifaceted approach to restore balance and healing function in the wound environment. Advanced therapies such as CTPs may be considered an effective option in combination with standard of care in setting a chronic wound on a course to closure.

References

  1. Rodrigues M, Kosaric N, Bonham CA, Gurtner GC. Wound healing: a cellular perspective. Physiol Rev. 2018;99:665-706.
  2. Atkin L, Bucko Z, Conde Montero E, et al. Implementing TIMERS: the race against hard-to-heal wounds. J Wound Care. 2019;28:3a.
  3. Wu SC, Marston W, Armstrong DG. Wound care: the role of advanced would healing technologies. J Vasc Surg. 2010;52(3 suppl):59S-66S.
  4. Høiby N, Bjarnsholt T, Moser C, et al. ESCMID guideline for the diagnosis and treatment of biofilm infections 2014. Clin Microbiol Infect. 2015;21:S1-S25. 10.1016/j.cmi.2014.10.024
  5. Zhao G, Usui ML, Lippman SI, James GA, et al. Biofilms and inflammation in chronic wounds. Adv Wound Care (New Rochelle). 2013;2(7):389-399.
  6. Schultz G, Bjarnsholt T, James GA, et al. Consensus guidelines for the identification and treatment of biofilms in chronic nonhealing wounds. Wound Repair Regen. 2017;25(5):744-757. doi:10.1111/wrr.12590
  7. Caley MP, Martins VL, O’Toole EA. Metalloproteinases and wound healing. Adv Wound Care (New Rochelle). 2015;4(4):225-234. https://doi.org/10.1089/wound.2014.0581
  8. Nuschke A. Activity of stem cells in therapies for chronic skin wound healing. Organogenesis. 2014;10(1):29-37.
  9. Dickinson LE, Gerecht S. Engineered biopolymeric scaffolds for chronic wound healing. Front Physiol. 2016;7:341. doi:10.3389/fphys.2016.00341
  10. Bohn G, Liden B, Schultz G, Yang Q, Gibson DJ. Ovine-based collagen matrix dressing: next-generation collagen dressing for wound care. Adv Wound Care (New Rochelle). 2016;5(1):1-10. doi: 10.1089/wound.2015.0660
  11. Chamanga ET. Clinical management of non-healing wounds. Nurs Stand. 2017;32(29):48-62.
  12. Stone RC, Stojadinovic O, Rosa AM, et al. A bioengineered living cell construct activates an acute wound healing response in venous leg ulcers. Sci Transl Med. 2017;9(371):eaaf8611. doi:10.1126/scitranslmed.aaf8611
  13. Milstone LM, Asgari MM, Schwartz PM, Hardin-Young J. Growth factor expression, healing, and structural characteristics of Graftskin (Apligraf®). Wounds. 2000;12(5 suppl A):12A-19A.
  14. Stone RC, Stojadinovic O, Sawaya AP, et al. A bioengineered living cell construct activates metallothionein/zinc/MMP8 and inhibits TGFβ to stimulate remodeling of fibrotic venous leg ulcers. Wound Repair Regen. 2019;28(2):164-176. doi:10.1111/wrr.12778

The views and opinions expressed in this blog are solely those of the author, and do not represent the views of WoundSource, HMP Global, its affiliates, or subsidiary companies.

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