Heterotopic Ossification and Hypertrophic Scars

Abstract

Burns and trauma lead to extensive superficial and deep soft tissue wounds which are unable to heal perfectly to the pre-injury state. Typically wound healing requires proliferation of cells capable of differentiating into the injured tissue type. As part of the structural requirements for tissue, these cells lay down extracellular matrix (ECM) often in the form of collagens. However, dysregulated cellular proliferation and collagen deposition often leads to wound pathology. Two conditions – heterotopic ossification (HO) and hypertrophic scarring – present a substantial challenge in the management of patients with large surface-area burns. HO is the pathologic formation of ectopic osseous lesions causing severe pain, non-healing wounds, and restricted range of motion. Current treatment strategies aimed at HO include prophylactic radiation therapy, non-steroidal anti-inflammatory drugs (NSAIDs), and bisphosphonates; ultimately patients who have developed HO may require surgical excision followed by prophylactic measures to reduce recurrence risk. Hypertrophic scars in contrast are non-osseous lesions caused by excessive collagen deposition. Similar to HO, hypertrophic scars are often painful, functionally limiting, and aesthetically displeasing. Treatment strategies include CO2 laser application, steroid injections, and excision with skin grafting. Here we review the biology, diagnosis, and treatment and outcomes associated with both forms of pathologic wound healing.

Coordinating Tissue Regeneration Through Transforming Growth Factor-β Activated Kinase 1 Inactivation and Reactivation

“…Patients with tHO are faced with debilitating pain, nonhealing wounds, and joint contractures limiting function . We have previously shown that tHO forms via endochondral ossification, and that inhibition of hypoxic signaling reduces tHO through its effects on cartilage production .…”

“…HO is a condition in which extraskeletal bone forms in response to local tissue injury; although HO has primarily been studied in the context of genetic mutations in type I bone morphogenetic protein receptors [14][15][16][17], it also is known to form in patients after severe trauma without genetic mutations (e.g., traumainduced HO [tHO]) [14,[18][19][20]. Recently, we have shown that tHO is caused by pathologic cellular proliferation and subsequent differentiation through a cartilaginous intermediary [14,20], prompting us to study transforming growth factor-β (TGF-β), a known mediator of cartilage formation [21][22][23][24][25][26][27], in HO.…”

Regulation of heterotopic ossification by monocytes in a mouse model of aberrant wound healing

“…After extremity trauma, an inflammatory response is mounted at the site of injury that promotes wound healing and regeneration of involved musculoskeletal tissues. However, severe trauma can lead to aberrant wound healing through mechanisms of dysregulated inflammation resulting in fibrosis or stem cell differentiation into a tissue distinct from its original fate, such as heterotopic ossification (HO), which commonly occurs after severe burn or trauma 3 . While the interaction between inflammatory cells and their effect on resident mesenchymal stem cells (MSCs) remains unclear, recent studies have identified MSCs capable of multi-lineage differentiation after injury 4 .…”

“…Primary outcome of interest for a priori power analysis is volume of mature ectopic bone formation. To detect 50% decrease from 7.5 mm 3 (with standard deviation of 2.2 mm 3 ) in untreated mice at significance level of 0.05 and power of 0.80, at least three mice were required per group. Means and SD were calculated from numerical data, as presented in text, figures, and figure legends.…”

Bioinformatics Analysis of the Molecular Mechanism of Late-Stage Heterotopic Ossification

“…Nearly all the acquired HO developed via endochondral ossification, a biological process usually seen in both bone development and fracture healing. The heterotopic endochondral ossification process triggers with injury/inflammatory, following mesenchymal stromal cell (MSC) recruitment, chondrogenic differentiation, and finally ossification formation [2]. For preventing HO, the inhibition of the chondrogenic differentiation process is most important considering the balance between promoting regeneration and suppression ossification; however, for treating the late-stage HO, the critical points may be the inhibition of osteogenesis and promoting ossification absorption.…”