Cellular- and Tissue-Based Products Versus Split-Thickness Skin Grafts: Which Are Superior?
Point
As these authors note, CTPs have numerous advantages over STSGs, including no donor-site morbidity, and also can be alternatives for patients with poor soft tissue envelopes.
By Dominick Casciato, DPM, and Jacob Wynes DPM, MS
From the acute surgical setting of muscle flaps and traumatic injury to chronic treatment of diabetic foot ulcers, an appreciation for wound closure is universal. When addressing large partial- and full-thickness wounds, split-thickness skin grafts (STSGs) allow for convenient and timely coverage.
Sustained and prompt closure of such wounds, however, remains the goal of any wound care program. As seen in research by Snyder and colleagues, the size of a diabetic foot ulcer at four weeks after initiating treatment predicted healing at 12 weeks.1 Such findings highlight the importance of recognizing and altering failed therapies with alternative treatment modalities. To address stagnation in wound healing, providers turned to advanced biologics, which over time found their utility as a first-line treatment either over or in addition to STSGs.
Such adjuvants, in the form of cellular- and tissue-based products (CTPs), serve as more than just a “skin-substitute” as their function reaches beyond simple wound coverage. Derived from human or animal tissue, dermoconductive CTPs may remain acellular and serve solely as a scaffolding for components integral for wound healing.2,3 Additionally, dermoinductive CTPs may contain living cells and actively participate in wound maturation through producing growth factors, cytokines, and collagen.2,3
In addition to providing the scaffolding for cellular components at the site of the wound, such products introduce chemical mediators to create and sustain a favorable environment to promote healing. From avoiding donor-site morbidity as a result of obtaining STSGs to providing alternatives for patients with poor soft tissue envelopes and healing potential at typical harvest sites, CTPs provide a host of advantages over the traditional autograft.
Why CTP Versus Autograft?
Compared to opening a sterile package to obtain a CTP, obtaining a STSG entails greater operative time for donor site preparation, dermatome use and meshing. Additionally, if the size of the graft is inadequate, additional passes may be necessary. As with all autograft procurement, inherent risks for pain, infection, and other complications exist following harvest.4,5 To minimize these occurrences, donor site dressings and postoperative instructions for care may be needed. Depending on the location and thickness of the STSG, donor site sensation may be permanently altered following harvest. Furthermore, STSGs are prone to contracture at the recipient site, and may require further supplementation if not large enough to cover soft tissue defect of concern.
Though split-thickness skin grafts provide wound coverage along with vasculature and chemical mediators obtained at the time of procurement, this is by no means a panacea for all wounds. By providing the recipient site with either dermoconductive or dermoinductive properties, CTPs have been efficacious in treating foot ulcers, venous leg wounds, and burns.6 While ulcers secondary to venous insufficiency, diabetic neuropathy, or ischemia share in their often chronic, non-healing nature, the unique precipitating etiologies are reflected in their respective wound beds. For example, ischemic ulcers maintain dry wound beds whereas venous leg ulcers may maintain a highly exudative bed—each necessitating biologics with unique properties.7
Some patients, however, may benefit from a combination of CTP and STSG. Papa and colleagues found higher TcPO2 in wound beds reconstructed by a combination of dermal substitute graft covered by STSG compared to STSG alone.8
Additionally, there is a role in which CTPs and autologous tissue could be used in tandem for soft tissue reconstruction.9 The most obvious is to build on a substrate and create a hospitable environment for eventual placement of autologous tissue such as STSG or full-thickness skin graft (FTSG). As a first-line treatment, when faced with a compromised host, the flexibility in performing a trial of CTP could further allow a clinician to gauge the wound substrate and avoid the potential premature failure of STSG application. Literature does support the use of native collagen prior to applying living skin substitutes to achieve optimal wound healing by modulation of harmful matrix metalloproteinases and through keratinocytes promoting the conversion of Type 1 collagen to gelatin, thereby facilitating the creation of robust granulation tissue.10
Further, various CTPs such as adult bovine collagen xenografts can be indicated for the use of exposed bone and tendon, which could be a limitation for STSG and FTSG.11 Lastly, large wounds might benefit from CTPs over autologous tissue coverage as these interventions typically result in decreased length of hospital stay and the need for extended patient recovery.12
Factors to Consider When Selecting an Appropriate CTP
A major benefit to CTPs is their ease of accessibility and use. As products may be stored in the clinic setting, applications remain relatively quick and efficient compared to a trip to the operating room. Prior to calling for your go-to shelved or in-stock CTP, however, one should understand the intricacies of the product. For example, appreciating graft thawing and application techniques—whether through bolster dressings, suturing, or adhesive bandages—optimizes CTP function. As some CTPs are covered by insurance and allow for multiple applications over the course of a set period, patient and graft selection should conducted with expiration in mind. For instance, certain bioengineered tissues with a shelf life of 10 days are typically not reapplied until four to six weeks after initial application.2,13,14
Beyond a dysvascular, malignant, or infected wound bed, one must consider any contraindications between the product and patient. Consideration should be given to patient allergies to components in CTPs as reactions have been reported though fish skin proves less immunogenic.15,16 Namely, religious beliefs may restrict the application of cadaver or animal products if other alternatives exist.17 Interestingly, fish skin maintains no cultural or religious barriers, and may serve as an alternative in such situations.18,19 As always, discussion and written consent prior to product application remain paramount prior to beginning treatment.
Final Thoughts
Regardless of CTP selection, wound bed preparation, optimization, and post-healing care remain paramount to achieve sustained healing. As hypoxia, ischemia, and infection discourage graft uptake, antagonistic local or systemic comorbidities should be addressed prior to product selection. Moreover, from offloading a healed neuropathic ulcer to stabilizing a flap covered with CTP using an external fixator, protecting the wound prone area must be considered. Overall, the wide selection of CTPs provides a defined composition and function to direct towards each wound environment. Other than in situations in which a STSG has failed, CTPs should not be seen as a replacement, but rather as an adjunctive to STSGs. Specifically, in conditions where one is unsure if a STSG will take, applying a CTP first will reduce any unnecessary donor site harvesting that can be used for a later graft if necessary.
In general, we do not believe that any modality should be used by itself and even Rodriguez-Collazo would agree that comprehensive limb salvage is rooted in principle in the ability to evolve from one modality to the next to achieve the most successful outcomes.20
Dr. Casciato is a Fellow at the University of Maryland Limb Preservation and Deformity Correction.
Dr. Wynes is an Assistant Professor in the Department of Orthopaedics at the University of Maryland School of Medicine. He is the Program Director of the Limb Preservation and Deformity Correction Fellowship.
Counterpoint
These authors argue that in contrast to the “skin substitute” of CTPs, a patient’s own human tissue offers superior healing, and is reliable and reproducible.
By Lauren L. Schnack, DPM, MS, AACFAS, FACPM, Sitong Chen, DPM, Stephanie Oexeman, DPM, AACFAS, DABPM, and Edgardo R. Rodriguez-Collazo, DPM
Split-thickness skin grafting (STSG) is an important part of the reconstructive ladder.1 It involves the transfer of the epidermis and part of the dermis from one part of the body to another. The purpose of this transfer is to cover active or chronic wounds resulting from burns, trauma, or reconstruction.2,3 When primary wound closure is not feasible, one would utilize a split-thickness skin graft for wound reconstruction.3 STSG coverage over a flap for complex wound coverage can a single stage or delayed procedure as well.3
The skin is the largest organ of the human body.3 Anatomically speaking, the outer layer of a STSG consists of the epidermis, which is made up of predominantly keratinocytes. This layer is very thin and serves as a barrier against pathogens, temperature, and excessive water loss.4 Also found in this layer are the adnexal structures such as hair follicles, sweat glands, and sebaceous glands, which penetrate into the deeper dermis. It is the stem cells from these structures that provide the progenitor cells for re-epithelialization. Deep to the epidermis is the dermis, which imparts strength and stability to the graft. This layer can be further divided into the papillary and reticular dermis. The papillary dermis is more superficial and consists of nerves and blood vessels. The deeper reticular dermis is composed of collagen fibers.5
One can harvest STSGs at varying degrees of thickness depending on the depth of dermis harvested, ranging from thin (0.008–0.012 inches), medium/intermediate (0.013–0.016 inches), and thick (0.017–0.02 inches). A mesher can also increase the surface area of the skin graft.3 A thinner STSG will have quicker incorporation, whereas the thicker STSG will have more structural integrity. A full thickness skin graft (FTSG) includes the epidermis and entire dermis, which is intended for smaller defects, with less risk of contracture.3
Choosing a Reconstruction Option
When referring to the plastic reconstructive ladder for lower limb defects created by trauma, tumor, chronic illness, etc., it is acceptable to address a simple wound defect by utilizing either a split-thickness skin graft or dermal substitute, healing by secondary intention, or primary closure. Note that a simple wound defect is defined by having no exposed bone, tendons, neurovascular structures, or present on the plantar skin.1
Contemporary grafting options consist of autografts, allografts, xenografts, artificial skin, and bioengineered skin.3 The current standard of care for addressing chronic, non-healing wounds is the harvest and application of a STSG.3,6 There are no currently available cellular- and tissue-based products (CTPs), formerly known as skin substitutes, able to replace all of the functions of human skin in which wound coverage would be needed for wound infection prevention and restoring the characteristics associated with the adjacent human skin. Cost and availability are barriers to CTP use.3
Harvesting of a STSG is a technique that can be replicated domestically and abroad with either a dermatome or Humbey knife. This can be performed in an operative theater setting or the clinic under local anesthesia with epinephrine. The authors prefer to harvest the STSG from the lateral calf or thigh and use a negative pressure wound therapy in order to prevent shearing of the graft and prevent hematoma or seroma formation on the recipient site. Typically, the donor sites take 2–3 weeks to heal.4
Unlike flaps, STSGs do not have their own blood supply and instead must rely on the underlying wound bed for profusion. The incorporation process can be broken down into the following three stages.
The first stage is imbibition. During the first 24–48 hours after graft application a thin film of fibrin and plasma separates the graft from the wound bed. At this stage, the graft appears white and ischemic. The graft is maintained solely by diffusion from the underlying tissue. It can survive in this stage up to a maximum of 4 days.3,7
The second stage is inosculation, in which there is the formation of a new vascular network between the wound bed and the existing severed graft vessels. The graft will start to appear pink at this stage, which typically occurs approximately 48 hours after placement.3,7
The third stage is revascularization, which begins on the fifth and sixth postoperative day, when additional vasculature to the wound bed has been established.3
In order to ensure optimal results, the donor site of the STSG should have an adequate superficial blood supply with acceptable metabolic activity. Cutaneous vasculature originates from the dermis and hypodermis, and the epidermis is an avascular tissue component.3 It is important to note that one can utilize a FLIR thermal camera (Teledyne FLIR) prior to any reconstructive procedure to evaluate vascular supply to a particular anatomical area.8 Grafts harvested from a highly perfused site will have a more optimal healing potential than a graft harvested from a poorly perfused site.3 When utilizing a graft or substitute, substituting “like tissue with like tissue” with an autograft rather than an allograft, will be optimal for healing. The wound should be debrided, free of infection and have a granular base.
Note that patients may have reservations or religious beliefs with the use of bioengineered cellular tissue products depending on their components, while the STSG requires a donor site, which is not aesthetically pleasing. Always have a thorough preoperative discussion of procedures and products and also ensure the patient understands the postoperative protocol. A donor site needs to heal by secondary intention. A systematic literature review on donor site morbidity for STSG harvested from the anterolateral thigh reported epithelialization could occur as early as 4 days after surgery, though epithelialization generally ranged from 1 to 3 weeks.9 The same study reported infection rates were generally low with 21 (47%) of the 46 studies reviewed reporting no infections in any treatment group.9 One must consider the donor site in the harvest of any autograft.
Final Thoughts
Split-thickness skin grafting is a reliable and reproducible procedure for simple defects and is often used in reconstructive flap procedures for lower extremity defects.3 Appropriate offloading and a nutritional diet high in protein are mandatory for any postoperative success, especially since skin is a metabolic regulator of protein and vitamin D metabolism.3
There are many options available for skin and wound closure, especially those that are industry driven. Cellular and tissue allografts or xenografts are often not readily available and are expensive. The harvesting and application of a STSG is the standard for simple non-infected wounds of the lower extremity due to the fact that it is an autograft and allografts and xenografts are unable to replicate the innate nature of the structures and function of the human tissue with bioengineered products.3 Split-thickness skin grafts are utilized in multiple surgical specialties outside of podiatric surgery, including but not limited to, dermatology, orthopedic traumatology, and plastic surgery.
There is no skin substitute that is superior to a patient’s own human tissue when harvested under the above-mentioned conditions.
Dr. Schnack is a Fellow at the Ascension Saint Joseph Hospital Chicago Fellowship in Complex Deformity Correction and Limb Reconstruction. She is board certified by the American Board of Podiatric Medicine and board qualified by the American Board of Foot and Ankle Surgery.
Dr. Chen is a third-year resident at Cooperman Barnabas Medical Center in Livingston, New Jersey.
Dr. Oexeman is a Fellowship-trained foot and ankle surgeon at Oexeman Foot and Ankle, PLLC. She is affiliated with Ascension Saint Joseph Hospital Chicago. She is board certified by the American Board of Podiatric Medicine and board qualified by the American Board of Foot and Ankle Surgery.
Dr. Rodriguez-Collazo is the Fellowship Director of the Ascension Saint Joseph Hospital Chicago Fellowship in Complex Deformity Correction and Limb Reconstruction.
Point References
1. Snyder RJ, Cardinal M, Dauphinée DM, Stavosky J. A post-hoc analysis of reduction in diabetic foot ulcer size at 4 weeks as a predictor of healing by 12 weeks. Ostomy Wound Manage. 2010 Mar 1;56(3):44–50.
2. Miller J, Wynes J. Updates on bioengineered alternative tissues. Clin Podiatr Med Surg. 2019 Jul;36(3):413–424. doi: 10.1016/j.cpm.2019.02.009. Epub 2019 Apr 8.
3. Steinberg JS, Werber B, Kim PJ. Bioengineered alternative tissues for the surgical management of diabetic foot ulceration. In: Zgonis T, editor. Surgical Reconstruction of the Diabetic Foot and Ankle. Philadelphia: Lippincott, Williams & Wilkins, 2009, pp. 105–9.
4. Chuenkongkaew T. Modification of split-thickness skin graft: cosmetic donor site and better recipient site. Ann Plast Surg. 2003;50:212–4.
5. Edwards J. Management of skin grafts and donor sites. Nurs Times. 2007;103:52–3.
6. Liu Y, Panayi AC, Bayer LR, Orgill DP. Current available cellular and tissue-based products for treatment of skin defects. Adv Skin Wound Care. 2019 Jan;32(1):19–25.
7. Jones JE, Nelson EA, Al-Hity A. Skin grafting for venous leg ulcers. Cochrane Database Syst Rev. 2013 Jan 31;2013(1):CD001737.
8. Papa G, Spazzapan L, Pangos M, Delpin A, Arnez ZM. Compared to coverage by STSG grafts only reconstruction by the dermal substitute Integra® plus STSG increases TcPO2 values in diabetic feet at 3 and 6 months after reconstruction. G Chir. 2014 May-Jun;35(5–6):141–5.
9. Shakir S, Messa CA 4th, Broach RB, et al. Indications and limitations of bilayer wound matrix-based lower extremity reconstruction: A multidisciplinary case-control study of 191 wounds. Plast Reconstr Surg. 2020 Mar;145(3):813–822.
10. Wahab N, Roman M, Chakravarthy D, Luttrell T. The use of a pure native collagen dressing for wound bed preparation prior to use of a living bi-layered skin substitute. J Am Coll Clin Wound Spec. 2015; 6(1–2):2–8.
11. Zhu B, Cao D, Xie J, Li H, Chen Z, Bao Q. Clinical experience of the use of Integra in combination with negative pressure wound therapy: an alternative method for the management of wounds with exposed bone or tendon. J Plast Surg Hand Surg. 2021 Feb;55(1):1-5.
12. Jeschke MG, Rose C, Angele P, Füchtmeier B, Nerlich MN, Bolder U. Development of new reconstructive techniques: use of Integra in combination with fibrin glue and negative-pressure therapy for reconstruction of acute and chronic wounds. Plast Reconstr Surg. 2004 Feb;113(2):525–30.
13. Redekop WK, McDonnell J, Verboom P, et al. The cost effectiveness of Apligraf treatment of diabetic foot ulcers. Pharmacoeconomics. 2003;21(16):1171–83.
14. Zaulyanov L, Kirsner RS. A review of a bi-layered living cell treatment (Apligraf) in the treatment of venous leg ulcers and diabetic foot ulcers. Clin Interv Aging. 2007;2(1):93–98.
15. Flynn A, Kilmartin D, Phelan S, McMenamin M, Kelly J, Laing ME. Delayed immunological reaction to Integra™ skin graft. Clin Exp Dermatol. 2019 Aug;44(6):714–716.
16. Fiakos G, Zeming K, Lo E. Improved skin regeneration with acellular fish skin grafts. Engineered Regeneration. 2020;1;95–101. Published 2020 Nov 1.
17. Eriksson A, Burcharth J, Rosenberg J. Animal derived products may conflict with religious patients’ beliefs. BMC Med Ethics. 2013;14:48. Published 2013 Dec 1.
18. Alam K, Jeffery SLA. Acellular fish skin grafts for management of split thickness donor sites and partial thickness burns: A case series. Mil Med. 2019 Mar 1;184(Suppl 1):16–20.
19. Wallner C, Holtermann J, Drysch M, et al. The use of intact fish skin as a novel treatment method for deep dermal burns following enzymatic debridement: A retrospective case-control study. Eur Burn J. 2022; 3(1):43–55.
20. Rodriguez Collazo ER, Rathbone CR, Barnes BR. A retrospective look at integrating a novel regenerative medicine approach in plastic limb reconstruction. Plast Reconstr Surg Glob Open. 2017 Jan 30;5(1):e1214.
Counterpoint References
1. AlMugaren FM, Pak CJ, Suh HP, Hong JP. Best local flaps for lower extremity reconstruction. Plast Reconstr Surg Global Open. 2020;8(4):1–8.
2. Wanner M, Adams C, Ratner D. Skin grafts. Flaps Grafts Dermatol Surg. 2007; 107–116.
3. Khan AA, Khan IM, Nguyen PP, Lo E, Chahadeh H, Cerniglia M, Noriega JA. Skin graft techniques. Clin Podiatr Med Surg. 2020;37(4):821–35.
4. Greenwood J, Amjadi M, Dearman B, Mackie I. Real-time demonstration of split skin graft inosculation and integra dermal matrix neovascularization using confocal laser scanning microscopy. Eplasty. 2009;e33:309–18.
5. Braza ME, Fahrenkopf MP. Split-Thickness Skin Grafts. 2022 May 8. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022.
6. Henning JA, Liette MD, Laklouk M, Fadel M, Masadeh S. The role of dermal regenerative templates in complex lower extremity wounds. Clin Podiatr Med Surg. 2020;37(4):803–20.
7. Thorne CH, Chung KC, Gosain AK, Gurtner GC, Mehrara BJ, Rubin JP, Spear SL. Grabb and Smith’s Plastic Surgery. Seventh Edition. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2013.
8. Pereira N, Valenzuela D, Mangelsdorff G, Kufeke M, Roa R. Detection of perforators for free flap planning using smartphone thermal imaging: a concordance study with computed tomographic angiography in 120 perforators. Plast Reconstr Surg. 2018;141(3):787–92.
9. Läuchli S, Hafner J, Ostheeren S, Mayer D, Barysch MJ, French LE. Management of split-thickness skin graft donor sites: a randomized controlled trial of calcium alginate versus polyurethane film dressing. Dermatology. 2013;227(4):361–6.
