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ORIGINAL ARTICLE Bali Medical Journal (Bali MedJ) 2021, Volume 10, Number 1: 225-228 P-ISSN.2089-1180, E-ISSN: 2302-2914 after orthopedic surgery: prevention, current therapy modalities, and

Published by Bali Medical Journal emerging therapies modalities

Andrew Sutheno1*

ABSTRACT

Keloid is a benign fibroproliferative tissue growth that exceeds the initial wound margins. It is caused by the disruption in the phase with increased activity and excess deposition. Keloid usually develops after 1Santo Antonius Hospital, West Kalimantan, Indonesia tissue trauma. Orthopedic surgery inevitably causes tissue trauma that will lead to the formation of in a few patients. Keloids can cause cosmetic and functional problems, thus interfere with a person’s quality of life. Keloid therapy modalities are mainly divided into three, which are prophylactic therapy modalities, current therapy modalities, and emerging therapy *Corresponding author: Andrew Sutheno; modalities that are being developed. This literature review aims to evaluate further prevention, current therapy modalities, Santo Antonius Hospital, and emerging therapies modalities in Keloid following orthopedic surgery. West Kalimantan, Indonesia; [email protected] Keywords: Keloid, Orthopaedic Surgery, Prevention, Management. Received: 2021-02-11 Cite This Article: Sutheno, A. 2021. Keloid after orthopedic surgery: prevention, current therapy modalities, and emerging Accepted: 2021-04-05 therapies modalities. Bali Medical Journal 10(1): 225-228. DOI: 10.15562/bmj.v10i1.2264 Published: 2021-04-28

INTRODUCTION PATHOGENESIS OF KELOID phase which can last for several months. Excess formation will Keloid is a benign fibroproliferative Keloids are considered the end product be degraded by matrix metalloproteinase tissue growth that exceeds the initial of the abnormal wound healing process. (MMP).6 wound margin in individuals with genetic In general, there are 3 phases of wound Abnormal fibroblast proliferation is the susceptibility without spontaneous healing that consist of the inflammatory 1,2 main basis for keloid formation. Keloid regression. The term ‘cheloid’ comes phase, the proliferation phase, and the proliferated more rapidly from Greek which means crab claws due remodeling phase. After the injury, platelet than fibroblasts from hypertrophic to the nature of the growth of keloid tissue degranulation, complement activation, 2,3 with higher collagen formation. Besides, that exceeds the initial wound margin. and a clotting cascade form fibrin clots increased inflammatory response and Keloid usually develops after tissue for hemostasis. Platelet degranulation imbalance between deposition and trauma. Orthopedic surgery inevitably will cause the release of various cytokines, degradation of the extracellular matrix causes tissue trauma that will lead to keloid including transforming growth factor-b 4 also play a role in the pathogenesis of formation in a few patients. Keloids can (TGF-b), platelet-derived growth factor keloids. There is a balance between cause cosmetic and functional problems. (PDGF), epidermal growth factor (EGF), the inflammatory, proliferation and Keloids often cause a cosmetic problem and insulin-like growth factor-1 (IGF-1), remodeling phases in the normal wound that leads to the embarrassment of the which play a role as a chemotactic agent healing process.2 In Keloid, there is a patient and decreased self-esteem. Most to recruit neutrophils, macrophages, prolonged inflammatory phase, increase importantly, keloids in joints can cause epithelial cells, mast cells, endothelial fibroblast activity, and excess deposition of joint contractures, thus limiting joint cells, and fibroblasts. Within 48-72 hours the extracellular matrix. This causes keloid movement. Problems that arise due to of injury, the wound healing process will tissue to grow beyond the margins of the keloids can interfere with a person’s quality enter a proliferation phase which can last initial wound.6 of life.5 3-6 weeks. Fibroblasts will synthesize Based on the brief explanation above, an extracellular matrix consisting of CLINICAL MANIFESTATION OF this literature study aims to review the procollagen, , proteoglycans, and KELOID prevention and management of Keloid hyaluronic acid, which functions to after orthopedic surgery. repair wound structures and form wound Keloid has the clinical appearance of a pink bridges. After the wound is closed, the to purplish solid mass with a shiny surface, wound healing phase enters a remodeling well-defined borders, and irregular edges.

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Keloids can be accompanied by and Patients diagnosed with keloids are at Silicon . The predilection for keloids is the an increased risk of arthrofibrosis after Silicone sheets can prevent wound chest, shoulders, earlobe, and upper primary total knee arthroplasty (TKA). stretching, provide occlusion, and hydrate arm. Keloids usually form after a tissue Arthrofibrosis is reported to be the the surface of the wound tissue. The trauma, although they can even form leading cause of TKA failure. Both keloids silicone sheet should be used as early as 2 spontaneously in the chest area without and arthrofibrosis are associated with an weeks from the start of the wound for more prior trauma. Keloid tissue grows beyond overexpression of TGF-b1. Patients who than 12 hours a day. This silicone sheet can the initial wound margin and there is no reported stiffness from arthrofibrosis be used for a minimum of 2 months.10 spontaneous regression.6 Keloids should be usually require surgical intervention such differentiated from hypertrophic scars. In as manipulation under anesthesia, which Flavonoid hypertrophic scars, the tissue formed consists of manipulating the knee through Flavonoids or bioflavonoids are natural does not exceed the initial wound margin a full range of motion while sedated. They substances from various plants that have and spontaneous regression may occur. are also at a higher risk of lysis of adhesion, been used to prevent the formation of heavy Hypertrophic scars are more common an open or arthroscopic approach to access scar tissue. Several studies have shown than keloids, with an incidence of 40-70% and debride adhesion.9 good results from using flavonoid gel on after surgery. Hypertrophic scars can be scars, but the efficacy of this product is observed 4-8 weeks after injury, develop TREATMENT OF KELOID controversial. The mechanism underlying rapidly for up to 6 months, then regress the use of flavonoids in scars is through the According to some recent literature, keloid gradually over several years.1,6 induction of matrix metalloproteinase-1 therapy modalities are mainly divided (MMP-1) and inhibition of small mothers into prophylaxis therapy, current therapy, PROBLEMS ARISING FROM against decapentaplegic 2 (SMAD 2), and emerging therapy modalities that are KELOID SMAD 3, SMAD 4 protein expression. being developed.5,10–12 The recommendation use of flavonoid is 2 Keloids can cause cosmetic and functional times a day for 4 to 6 months.10 problems.5 A study by Gürbüz et al. A. PROPHYLAXIS THERAPY showed that children with elbow fractures Skin Incision along the Main Folding B. CURRENT THERAPY accompanied by keloid lesions should Lines MODALITIES be followed up for possible neurologic The formation of and deficits with late-onset.7 The causative acetonide (TA) keloids could be prevented by making factor of late-onset neurologic deficits is Intralesional TA injection is the most the skin incisions along the main folding the penetration of the to the nerve frequently used therapeutic modality for lines.13,14 The skin tension lines depend and neural . Neural fibrosis could keloid management, but it is estimated on the interrelation of elastic fibers and be precipitated by excessive fibroblastic that 50% of keloids are resistant to steroid collagen fibers and the anchorage of activity.7 Most importantly, keloids in therapy.15 works collagen bundles on each other. Incisions joints can cause joint contractures, thus by suppressing the inflammatory process, parallel to folds separate the collagen limiting joint movement.5 decreasing fibroblast proliferation, and bundles longitudinally and heal without Keloids often cause a cosmetic problem decreasing collagen synthesis. Side retraction. A linear incision develops a that leads to the embarrassment of the effects of TA that often occur include wider gape if it occurs transversely to the patient and decreased self-esteem. A telangiectasis, hypopigmentation, and skin main folding lines.13 study by Motoki et al. shows that 40% of . These side effects were reported keloid patients have a negative picture of Compression Therapy to be reduced when combined with their bodies.8 In addition, keloid patients 5- for keloid management.16 Wound compression with a pressure of may have body dysmorphic disorders 15-40 mmHg for more than 23 hours because pathological scar tissue causes 5-Fluorouracil (5-FU) a day for at least 6 months has been dissatisfaction with self-image. This 5-fluorouracil is a pyrimidine analog that said to prevent keloids. Although this can interfere with the patient’s social inhibits DNA synthesis by irreversibly pressure therapy reduces scar tissue’s relationships with other people.8 Keloids inhibiting the thymidine synthase subjective and objective complaints, can cause anxiety disorders, depression, enzyme, which triggers fibroblast the scientific evidence supporting its and disruption to a patient’s daily routine. apoptosis and scar degradation.17 The clinical effectiveness is controversial. The Problems that arise due to keloids can 5-FU concentration commonly used as mechanism of pressure therapy to prevent impair a person’s quality of life.5 a keloid monotherapy agent is 50 mg/ keloids has not been elucidated, but it is ml. Fitzpatrick recommends a one-week hypothesized that pressure therapy can KELOID IS A PREDICTOR interval between intralesional 5-FU cause occlusion of blood vessels, thereby OF COMPLICATION IN injections for the management of keloids. limiting oxygen intake from blood vessels ORTHOPAEDIC SURGERY The use of intralesional 5-FU injection as to the injured tissue, which leads to a monotherapy agent in the management Keloids could also act as a predictor of increased apoptosis.10 of keloids has been reported to be good for complications in orthopedic surgery.

226 Published by Bali Medical Journal | Bali Medical Journal 2021; 10(1): 225-228 | doi: 10.15562/bmj.v10i1.2264 ORIGINAL ARTICLE

45-78% of patients.18 to blood vessels, thereby inhibiting the shows good cosmetic results. Side effects delivery of inflammatory cytokines to reported include , erosion, and Surgery scar revision the keloid tissue. Side effects that can crust formation. A meta-analysis in 2017 Scar revision with surgical excision of arise from a laser are , estimated the recurrence of keloids in the Keloid should be performed with hypopigmentation, bullae formation, and patients receiving imiquimod cream after minimal tension at the time of wound purpura.20 surgery was 24.7%.11 closure. The recurrence rate of keloids after scar revision with surgical excision C. EMERGING THERAPY Tamoxifen is reported to be high, namely 45-100%. MODALITIES Tamoxifen is an anti-estrogen agent used This surgical excision scar revision often in the management of breast cancer. In must be combined with other therapeutic the in vitro studies, tamoxifen decreased Interferon consists of cytokines that modalities, such as steroid injection TGF-b1 production, inhibited the have anti-proliferative and anti-fibrotic and radiotherapy to prevent keloid proliferation of keloid fibroblasts, and effects. Interferon will decrease collagen recurrence.10 decreased collagen synthesis. A clinical synthesis and fibroblast proliferation by study in 13 keloid patients injected with decreasing TGF-b1 expression. Interferon tamoxifen 20 mmol/L once a week for 8 intralesional injection is usually used at a Cryotherapy has been used to manage weeks showed a reduction in the number of dose of 1.5 million IU, 2 times a day for keloids, both as a single therapeutic agent keloid fibroblasts on the histopathological 4 days. The side effects reported are pain or in combination with other therapies examination compared to before therapy.11 at the injection site and flu-like symptoms. such as intralesional TA injection. Besides, the collagen structure is also Although interferon is an expensive Cryotherapy could induce tissue necrosis found to be atrophic.11 therapy for keloids, it has become a due to vascular damage, thus can be used promising therapeutic modality.21 as a keloid therapy. Cryotherapy success Type-A Botulinum toxin rates are reported to be 32-74% after Bleomycin Botulinum toxin derived from Clostridium several therapy sessions.10 botulinum is a neurotoxin that inhibits Bleomycin is a cytotoxic, anti-neoplastic, neuromuscular transmission. Several anti-viral, and anti-bacterial agent derived Radiotherapy studies have shown that botulinum toxin from Streptomyces verticillus. Bleomycin Radiotherapy is generally performed as type A can minimize scar formation by could reduce collagen synthesis and adjuvant therapy and is performed 24- reducing muscle tension during wound induced apoptosis. Bleomycin 1.5 IU / 48 hours after surgical scar revision. The healing. In addition, botulinum toxin can ml was given by intralesional injection radiation dose used is 40 Gray which is cause the cell cycle to stop at G0 or G1 and 1 month apart. Generally, it takes 2-6 divided into several therapy sessions to affect TGF-b1 expression. Intralesional sessions. Several studies have shown minimize side effects. Radiotherapy is botulinum toxin injection at a dose of 70- complete keloid depletion in 54-73% thought to have an anti-angiogenetic effect 140 U per session at intervals of 1-3 months of keloid patients and relief of keloid so that it can be used in the management for 3 sessions showed improvement symptoms such as itching and pain. Side of keloids. Inhibition of angiogenesis in keloid lesions and decreased Keloid effects that can be found are pain on will reduce inflammatory cytokines and subjective symptoms itching and pain.10,22 injection, ulceration, hyperpigmentation, inhibit fibroblast activity, thereby reducing and skin atrophy. Systemic side effects collagen synthesis and suppressing keloid Captopril have not been reported.10 formation. The unwanted side effect Research by Chen et al. shows that captopril that arises from radiotherapy is the risk Verapamil can reduce the production of angiotensin of carcinogenesis. In one study, keloid II, collagen, and cellular proliferation Verapamil is a calcium channel blocker recurrence with radiotherapy was reported in keloid fibroblast cultures at certain that is used as an anti-hypertensive agent. to be 9.59%.10,19 effective concentrations.23 Captopril also Verapamil works by decreasing collagen dramatically decreased the expression of production, stimulating collagenase Laser TGF-b1, PDGF, and heat shock protein synthesis, and reducing fibrotic tissue The first laser therapy was used for keloid 47 (HSP47) in keloid fibroblasts. Through production. There were no systemic therapy in 1980. The most commonly these various mechanisms, captopril side effects associated with intralesional used laser for keloid therapy is the has been shown to inhibit fibroblast verapamil injection.21 pulsed dye laser with a wavelength of proliferation and collagen synthesis, 585 nm. Another laser frequently used Imiquimod which plays a role in keloid formation. for keloid management is the 1064 nm This makes captopril a potential drug to Imiquimod, 5% cream, can be used as neodymium-doped yttrium aluminum be used as a modality for keloid therapy.23 a therapeutic agent for keloids because garnet (Nd: YAG) laser. Several sessions it promotes apoptosis. The use of 5% of laser therapy are required for keloid Mesenchymal stem cell imiquimod cream after excision of management. The laser will cause damage Mesenchymal stem cells have the Keloid on the ear lobe for 6 weeks immunomodulatory and anti-fibrotic

Published by Bali Medical Journal | Bali Medical Journal 2021; 10(1): 225-228 | doi: 10.15562/bmj.v10i1.2264 227 ORIGINAL ARTICLE

effects. The anti-fibrotic effectthe of literature, as well as data analysis and Main Folding Lines. J Bone Jt Surg. mesenchymal stem cells in various fibrotic interprets the study through publication. 2019;101:392–9. diseases such as myocardial infarction, 14. Rennekampff HO, Tenenhaus M. renal fibrosis, or cirrhosis of the liver REFERENCES Theoretical basis for optimal surgical incision planning to reduce hypertrophic has been reported. Mesenchymal stem 1. Shaheen A. Comprehensive review of scar formation. Med Hypotheses cells can reduce the excess inflammatory keloid formation. Clin Res Dermatol. [Internet]. 2020;140:1–4. process that occurs in keloids. This therapy 2018;4(5):1–18. 15. Hietanen KE, Järvinen TA, Huhtala can be given by systemic injection or local 2. Mari W, Alsabri SG, Tabal N, Younes H, Tolonen TT, Kuokkanen HO, injection to the wound, intradermal, or S, Sherif A, Simman R. Novel insights Kaartinen IS. Treatment of keloid scars subcutaneous. 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Gauglitz G, Bureik D, Dombrowski Y, There is no competing interest regarding 11. Huang C, Liu L, You Z, Du Y, Ogawa R. Pavicic T, Ruzicka T, Schauber J. Botulinum the manuscript. Managing keloid scars : from radiation toxin A for the treatment of keloids. Ski therapy to actual and potential drug Pharmacol Physiol. 2012;25:313–8. FUNDING deliveries. Int Wound J. 2019;1–8. 23. Chen J, Zhao S, Liu Y, Cen Y, Nicolas C. 12. Tripathi S, Soni K, Agrawal P, Gour V, Effect of captopril on collagen metabolisms None. Mondal R, Soni V. Hypertrophic scars and in keloid fibroblast cells. ANZ J Surg. keloids : a review and current treatment 2016;86(12):1046–51. AUTHOR CONTRIBUTION modalities. Biomed . 2020;4:1–11. Andrew Sutheno is responsible for this 13. Lemperle G, Knapp D, Tenenhaus literature study from the conceptual M. Minimal Scar Formation After framework, data acquisition, selecting Orthopaedic Skin Incisions Along

228 Published by Bali Medical Journal | Bali Medical Journal 2021; 10(1): 225-228 | doi: 10.15562/bmj.v10i1.2264