Hypertrophic scarring: the greatest unmet challenge after burn injury

doi:10.1016/S0140-6736(16)31406-4

The Lancet

Volume 388, Issue 10052, 1–7 October 2016, Pages 1427-1436

https://doi.org/10.1016/S0140-6736(16)31406-4 Get rights and content

Summary

Improvements in acute burn care have enabled patients to survive massive burns that would have once been fatal. Now up to 70% of patients develop hypertrophic scars after burns. The functional and psychosocial sequelae remain a major rehabilitative challenge, decreasing quality of life and delaying reintegration into society. Approaches to optimise healing potential of burn wounds use targeted wound care and surgery to minimise the development of hypertrophic scarring. Such approaches often fail, and modulation of the established scar is continued although the optimal indication, timing, and combination of therapies have yet to be established. The need for novel treatments is paramount, and future efforts to improve outcomes and quality of life should include optimisation of wound healing to attenuate or prevent hypertrophic scarring, well-designed trials to confirm treatment efficacy, and further elucidation of molecular mechanisms to allow development of new preventive and therapeutic strategies.

Introduction

Cutaneous scarring remains the pathognomonic feature after burns to the skin and characteristically underlies post-burn physical and psychosocial morbidity. The most common cicatrix formed after a burn is the hypertrophic scar, the prevalence of which is reportedly as high as 70%.¹ During the past several decades, improvement in acute burn care has reduced mortality, enabling survival of burn injuries covering up to 100% of total body surface area (TBSA). Patients with these massive burns have extensive scarring and contractures, restricted movement, itch, and pain, might be dissatisfied with their appearance, and have loss of function for many years. The greatest unmet challenges in burn rehabilitation are decreased quality of life and delayed reintegration into society resulting from post-burn scar. In this second article in a Series on burns, we discuss strategies for burn wound and scar management and identify areas that need more research to reduce post-burn scarring and improve burn survivors’ rehabilitation and reintegration into society.

Section snippets

Post-burn scarring

After cutaneous injury, the defect is healed through creation of a scar, with linear collagen deposition lacking the flexibility of uninjured skin. Although the desired result for any healing wound is scarless healing, the best result is usually a flat, pliable scar, with slight discoloration. Deposition of excess collagen results in a pathological scar that is thick, non-pliable, itchy, and painful.² Two types of pathological scars can arise from the burn wound—a hypertrophic scar or a keloid.

Pathophysiology of wound healing and scarring

In postnatal tissue, wound healing occurs in three discrete phases that ultimately result in the formation of a scar: inflammation, proliferation, and remodelling.⁸ Modulation of the three phases can allow the wound to heal without scar or result in excessive fibrosis. Although a flat, less fibrotic scar is desired, when the acute inflammatory phase persists or wound healing is delayed, pathological scars form (panel). During the inflammatory phase, a fibrin clot forms, thereby creating a

Acute wound care

Clinical evidence suggests that time to healing is associated with burn wound depth. Most burn wounds—flash injuries and small scalds—are superficial second degree (partial-thickness) burns that usually result in an unobtrusive, non-hypertrophic scar.13, 14 Delayed healing of these wounds might result from infection or a known permutation of wound healing, such as diabetes or systemic corticosteroid use.¹⁵ Care for such wounds consists of washing with water and chlorhexidine or hand soap (an

Assessment of the impact of scar

To determine whether interventions are successful and effective in modulating burn scar, objective assessment techniques and experimental models are used. Although improvements in developing less subjective assessment techniques and more clinically relevant experimental models have provided the community with improved tools to study post-burn scarring, room for improvement remains. The impact of the scar cannot be fully understood through physical examination or histological evaluation.

Models to study post-burn scar

Elucidation of molecular mechanisms underlying hypertrophic scar, and effects of therapeutic interventions on the scarring process, has been limited largely to biopsies from human patients used for histology or derivation of skin cultures or cell cultures. The scarcity of animal models that heal and scar similarly to people has hindered research; however, several animal models have been developed that enable studies of hypertrophic scar. Female (or castrated male) red Duroc pigs develop

Non-surgical approaches to scar modification

Compression garments, massage, laser therapy, intense pulsed light, steroids, exercise, and injection of fat into the scar have been used to reduce hypertrophic scar.⁸⁶ Because these therapies are not wholly effective on their own, patients might benefit from a combination of several approaches. If the scar remains problematic after manipulation, surgical revision is used to correct deficiencies and deformities. There is a paucity of data for cost-effectiveness of all burn scar treatments and

Genetics of burn scar

Although elucidation of the genetic component to scarring is in its infancy, DNA genotyping has been used to identify the variant genes associated with severity of hypertrophic scar. In a study¹¹⁴ of predominantly white males, a particular variant of the CUB and Sushi multiple domains 1 (CSMD1) gene was associated with less severe post-burn hypertrophic scarring. The protein produced by CSMD1 is a putative tumour suppressor, the expression of which is elevated in cells isolated from head and

Conclusion

Despite shortcomings of many studies on hypertrophic scarring, the studies we have presented in this Series paper have altered clinical care such that methods used to heal burn wounds and reduce post-burn hypertrophic scar are improving. When a severely burned patient is treated, prevention of hypertrophic scar is preferred over treatment of a resultant scar. The current approach of reducing hypertrophic scar formation with early acute surgical intervention and various non-surgical modalities,

Search strategy and selection criteria

We searched PubMed for English language manuscripts published between January, 2006 and April, 2016, with combinations of the keywords “burn”, “thermal”, “cicatrix”, “hypertrophic”, and “keloid” in the abstract, title, or both. From this search result, we preferentially selected manuscripts in which large cohorts of patients with appropriate control groups had been studied. Because of the limitations on space, we cited review articles from the past 5–10 years—as opposed to primary

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Mesenchymal stem cell (MSC)-based therapy is an effective strategy for regenerative therapy. However, safety and ease of use are still issues to be overcome in clinical applications. Exosomes are naturally derived nanoparticles containing bioactive molecules, which serve as ideal cell-free therapeutic modalities. However, issues such as delivery, long-term preservation and activity maintenance of exosomes are other problems that limit their application. In this study, we proposed the use of rapid freeze-dry-thaw macroporous hydrogels for the encapsulation of HucMSC-derived exosomes (HucMSC-Exos) combined with an antimicrobial peptide coating. This exosome-encapsulated hyaluronic acid macroporous hydrogel HD-DP7/Exo can achieve long-term storage and transport by lyophilization and can be rapidly redissolved for treatment. After comprehensively comparing the therapeutic effects of HucMSC-Exos and HucMSC-loaded hydrogels, we found that HucMSC-Exos could also effectively regulate fibroblasts, vascular endothelial cells, and macrophages and inhibit myofibroblast-mediated fibrosis, thus promoting tissue regeneration and inhibiting scar formation in a mouse model of deep second-degree burn infection healing. These properties of lyophilized storage and whole-process-repair make HD-DP7/Exo have potential application value and application prospects.
Layered dissolving microneedle containing a three-drug combination on the treatment of hypertrophic scar
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Hypertrophic scars (HS), mainly caused by burns, trauma, and surgery, are associated with erythema, bumps, itching, and pain. The oral administration of Asiaticoside (AS) is a prevalent treatment for HS in clinical settings; however, its effectiveness is constrained due to its low bioavailability, necessitating high dosages for therapeutic impact. To mitigate this issue, we developed a layered dissolving microneedle (DMN) incorporating AS–ginsenoside Rb1–L–carnosine (A–G–C) at the tip for HS treatment. The tip layer of the DMNs comprised sodium carboxymethyl cellulose (CMC), while the base layer consisted of low-viscosity CMC to enhance mechanical strength. We examined its puncture performance, in vitro dissolution ability, and therapeutic effect on a rabbit ear model of HS. Histological analysis was performed by Hematoxylin and Eosin (H&E), Masson staining and Sirius red staining. The results demonstrated that the DMNs exhibited excellent puncture performance and dissolution rates. A-G-C DMNs were found to be effective in reducing scar thickness by measuring scar thickness changes. Histological analysis revealed that the A–G–C DMNs significantly reduced inflammation and collagen fiber deposition in scar tissue. Importantly, the therapeutic effect achieved with A–G–C DMNs was comparable to that of triamcinolone acetonide injection. These findings highlight the potential of DMNs loaded with A–G–C as a promising treatment modality for HS, offering improved bioavailability and therapeutic outcomes.
NovoSorb® Biodegradable Temporising Matrix (BTM): What we learned from the first 300 consecutive cases
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Extensive full-thickness soft-tissue defects remain a challenge in reconstructive surgery. NovoSorb® Biodegradable Temporising Matrix (BTM) represents a novel dermal substitute and was evaluated in wounds deriving from different aetiologies and to highlight risk factors for poor take rates.
All patients treated with BTM at our department between March 2020 and October 2022 were included. Differences in univariate and linear regression models identified predictors and risk factors for take rates of BTM and split-thickness skin grafts (STSG).
Three hundred patients (mean age 54.2 ± 20.1 years, 66.3% male, 59.7% burns, 19.7% trauma and 20.6% others) were evaluated. Mean take rates of BTM and STSG after BTM delamination were 82.7 ± 25.2% and 86.0 ± 22.6%, respectively. Multiple regression analyses showed that higher body mass index (BMI, OR 0.43, 95% CI 0.86, −0.01, p = 0.44), prior allograft transplantation (OR 15.12, 95% CI 26.98, −3.31, p = 0.041), longer trauma-to-BTM-application intervals (OR 0.01, 95% CI 0.001, −0.001, p = 0.038), positive wound swabs before BTM (OR 7.15, 95% CI 13.50, −0.80, p = 0.028) and peripheral artery disease (OR 10.80, 95% CI 18.63, −2.96, p = 0.007) were associated with poorer BTM take. Higher BMI (OR 0.40, 95% CI 0.76, −0.08, p = 0.026), increasing BTM graft surface areas (OR 0.58, 95% CI −1.00, −0.17, p = 0.005), prior allograft (OR 12.20, 95% CI −21.99, −2.41, p = 0.015) or autograft transplantations (OR 22.42, 95% CI 38.69, −6.14, p = 0.001), tumour as the aetiology of the wound (OR 37.42, 95% CI 57.41, −17.83, p = 0.001), diabetes (OR 6.64, 95% CI 12.80, −0.48, p = 0.035) and impaired kidney function (OR 5.90, 95% CI 10.94, −0.86, p = 0.021) were associated with poorer STSG take after delamination of BTM, whereas higher BTM take rates were associated with better STSG take (OR 0.40, 95% CI 0.31,0.50, p < 0.001).
Extensive complex wounds of different aetiologies unsuitable for immediate STSG can be successfully reconstructed by means of two-staged BTM application and subsequent skin grafting. Importantly, presence of wound contamination or infection and prior allograft coverage appear to jeopardise good BTM and STSG take.
Global proteomic analysis reveals lysine succinylation is involved in the pathogenesis of hypertrophic scar
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Lysine succinylation (Ksucc) is a recently identified posttranslational modification that is involved in many diseases. This study examined the role of Ksucc in the pathogenesis of hypertrophic scar (HS). The presence of Ksucc in human skin was measured by immunoblotting. Ksucc occurs in many skin proteins ranging from 25 to 250 kDa, and higher levels of Ksucc are found in HS skin than in normal skin. An immunoaffinity approach coupled with LC–MS/MS was used to characterize the first succinylome of human skin, and 159 Ksucc sites in 79 proteins were identified. Among these, there were 38 increased succinylated sites in 29 proteins but no decreased succinylated sites in HS compared with normal skin. A parallel reaction monitoring assay was performed to validate the results of the succinylome and showed that the levels of Ksucc in decorin and collagens, which are involved in the pathogenesis of HS, were increased in HS than in normal skin. In addition, increasing the level of Ksucc enhanced cell proliferation and upregulated the expression of fibrosis markers (α-SMA, COL1, and COL3) in human skin fibroblasts. Our results provide global insights into the functional role of Ksucc in hypertrophic scarring.
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Hypertrophic scar (HTS) is a prevalent chronic inflammatory skin disorder characterized by abnormal proliferation and extracellular matrix deposition and the precise mechanisms underlying HTS remain elusive. This study aimed to identify and validate potential immune-related genes associated with hypertrophic scar formation.
Skin samples from normal (n = 12) and hypertrophic scar tissues (n = 12) were subjected to RNA-seq analysis. Differentially expressed genes (DEGs) and significant modular genes in Weighted gene Co-expression Network Analysis (WGCNA) were identified. Subsequently, functional enrichment analysis was performed on the intersecting genes. Additionally, eight immune-related genes were matched from the ImmPort database. Validation of NRG1 and CRLF1 was carried out using an external cohort (GSE136906). Furthermore, the association between these two genes and immune cells was assessed by Spearman correlation analysis. Finally, RNA was extracted from normal and hypertrophic scar samples, and RT-qPCR, Immunohistochemistry staining and Western Blot were employed to validate the expression of characteristic genes.
A total of 940 DEGs were identified between HTS and normal samples, and 288 key module genes were uncovered via WGCNA. Enrichment analysis in key module revealed involvement in many immune-related pathways, such as Th17 cell differentiation, antigen processing and presentation and B cell receptor signaling pathway. The eight immune-related genes (IFI30, NR2F2, NRG1, ESM1, NFATC2, CRLF1, COLEC12 and IL6) were identified by matching from the ImmPort database. Notably, we observed that activated mast cell positively correlated with CRLF1 expression, while CD8 T cells exhibited a positive correlation with NRG1. The expression of NRG1 and CRLF1 was further validated in clinical samples.
In this study, two key immune-related genes (CRLF1 and NRG1) were identified as characteristic genes associated with HTS. These findings provide valuable insights into the immune-related mechanisms underlying hypertrophic scar formation.

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SeriesHypertrophic scarring: the greatest unmet challenge after burn injury

Summary

Introduction

Section snippets

Post-burn scarring

Pathophysiology of wound healing and scarring

Acute wound care

Assessment of the impact of scar

Models to study post-burn scar

Non-surgical approaches to scar modification

Genetics of burn scar

Conclusion

Search strategy and selection criteria

Burns

Surg Clin North Am

Burns

Burns

Surg Clin North Am

Burns

Clin Plast Surg

Burns

Burns

Burns

Clin Plast Surg

Burns

Burns

Burns Incl Therm Inj

Burns

Burns

Burns

J Plast Reconstr Aesthet Surg

Burns

Burns

Burns

J Surg Res

Burns

Burns

Lab Invest

J Am Coll Certif Wound Spec

Burns

Burns

Burns

J Plast Reconstr Aesthet Surg

J Plast Reconstr Aesthet Surg

On the nature of hypertrophic scars and keloids: a review

Plast Reconstr Surg

The most current algorithms for the treatment and prevention of hypertrophic scars and keloids

Plast Reconstr Surg

Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies

Mol Med

Keloids and scars: a review of keloids and scars, their pathogenesis, risk factors, and management

Curr Opin Pediatr

Hypertrophic versus non hypertrophic scars compared by immunohistochemistry and laser confocal microscopy: type I and III collagens

Int Wound J

Overview of surgical scar prevention and management

J Korean Med Sci

Scar prevention and remodeling: a review of the medical, surgical, topical and light treatment approaches

Int J Dermatol

Hypertrophic burn scars: analysis of variables

J Trauma

Factors affecting wound healing

J Dent Res

Are topical antimicrobials effective against bacteria that are highly resistant to systemic antibiotics?

J Burn Care Res

Nonsilver treatment vs. silver sulfadiazine in treatment of partial-thickness burn wounds in children: a systematic review and meta-analysis

Wound Repair Regen

Dressings for superficial and partial thickness burns

Cochrane Database Syst Rev

Scarring occurs at a critical depth of skin injury: precise measurement in a graduated dermal scratch in human volunteers

Plast Reconstr Surg

Critical review of burn depth assessment techniques: part II. Review of laser doppler technology

J Burn Care Res

A new concept in the early excision and immediate grafting of burns

J Trauma

A comparison of conservative versus early excision. Therapies in severely burned patients

Ann Surg

Longitudinal assessment of Integra in primary burn management: a randomized pediatric clinical trial

Crit Care Med

Multicenter postapproval clinical trial of Integra dermal regeneration template for burn treatment

J Burn Care Rehabil

Series
Hypertrophic scarring: the greatest unmet challenge after burn injury