Wound Healing: Cellular Review With Specific Attention to Postamputation Care
Wound healing is crucial for survival, prevention of infection, and restoration of tissue function. The immune system drives this process with 3 main phases: inflammation, proliferation, and remodeling. Keloids and hypertrophic scars reveal disruptions in these phases, underscoring the balance needed for healing. Limb amputation, a life-changing event, demands careful consideration for healing and function. Factors such as amputation level, surgical technique, and prosthetic fitting shape outcomes, while complications such as heterotopic ossification challenge recovery. Treatment advances including statins and stem cell therapy hold promise, with dermatologists poised to contribute substantially to postamputation care.
Practice Points
- Wound healing in adults is a complex dynamic process that usually takes the greater part of 1 year to completely resolve and is marked by the end of scar formation.
- Postamputation residual limbs are subject to mechanical and biophysical stress to which the overlying skin is not accustomed. Skin treatment aims at mitigating these stresses.
- The major dermatologic barriers to successful wound healing following amputation include infection, skin breakdown, formation of chronic wounds and granulation tissue, heterotopic ossification, and hyperhidrosis.
The eventual outcome of the remodeling phase determines the appearance and functionality of the healed tissue. Any disruption in this phase can lead to complications, such as chronic wounds and hypertrophic scars/keloids.4-6 These abnormal healing processes are characterized by localized inflammation, heightened fibroblast function, and excessive accumulation of the extracellular matrix.4-8
Molecular Mechanisms
Comprehensive investigations—both in vivo and in vitro—have explored the intricate molecular mechanisms involved in heightened wound healing. Transforming growth factor β takes center stage as a crucial factor, prompting the transformation of fibroblasts into myofibroblasts and contributing to the deposition of extracellular matrix.2,4-8,10 Transforming growth factor β activates non-Smad signaling pathways, such as MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide 3-kinase), influencing processes associated with fibrosis.5,11 Furthermore, microRNAs play a pivotal role in posttranscriptional regulation, influencing both transforming growth factor β signaling and fibroblast behavior.12-16
The involvement of prostaglandins is crucial in wound healing. Prostaglandin E2 plays a notable role and is positively correlated with the rate of wound healing.5 The cyclooxygenase pathway, pivotal for prostaglandin synthesis, becomes a target for inflammation control.4,5,10 Although aspirin and nonsteroidal anti-inflammatory drugs commonly are employed, their impact on wound healing remains controversial, as inhibition of cyclooxygenase may disrupt normal repair processes.5,17,18
Wound healing exhibits variations depending on age. Fetal skin regeneration is marked by the restoration of normal dermal architecture, including adnexal structures, nerves, vessels, and muscle.4-6 The distinctive characteristics of fetal wound healing include a unique profile of growth factors, a diminished inflammatory response, reduced biomechanical stress, and a distinct extracellular matrix composition.19 These factors contribute to a lower propensity for scar formation compared to the healing processes observed in adults. Fetal and adult wound healing differ fundamentally in their extracellular matrix composition, inflammatory cells, and cytokine levels.4-6,19 Adult wounds feature myofibroblasts, which are absent in fetal wounds, contributing to heightened mechanical tension.5 Delving deeper into the biochemical basis of fetal wound healing holds promise for mitigating scar formation in adults.
Takeaways From Other Species
Much of the biochemical knowledge of wound healing, especially regenerative wound healing, is known from other species. Geckos provide a unique model for studying regenerative repair in tails and nonregenerative healing in limbs after amputation. Scar-free wound healing is characterized by rapid wound closure, delayed blood vessel development, and collagen deposition, which contrasts with the hypervascular granulation tissue seen in scarring wounds.20 Scar-free wound healing and regeneration are intrinsic properties of the lizard tail and are unaffected by the location or method of detachment.21
Compared to amphibians with extraordinary regenerative capacity, data suggest the lack of regenerative capacity in mammals may come from a desynchronization of the fine-tuned interplay of progenitor cells such as blastema and differentiated cells.22,23 In mice, the response to amputation is specific to the level: cutting through the distal third of the terminal phalanx elicits a regeneration response, yielding a new digit tip resembling the lost one, while an amputation through the distal third of the intermediate phalanx triggers a wound healing and scarring response.24
Wound Healing Following Limb Amputation
Limb amputation represents a profound change in an individual’s life, impacting daily activities and overall well-being. There are many causes of amputation, but the most common include cardiovascular diseases, diabetes mellitus, cancer, and trauma.25-27 Trauma represents a relatively common cause within the US Military due to the overall young population as well as inherent risks of uniformed service.25,27 Advances in protective gear and combat casualty care have led to an increased number of individuals surviving with extremity injuries requiring amputation, particularly among younger service members, with a subgroup experiencing multiple amputations.27-29
