Adipose-Based Therapeutics and Transplantation of Hypodermis

Abstract

Significance:

Wound healing is a complex process, and while the epidermis and dermis receive significant attention, the role of the hypodermis is important. The adipose-rich hypodermis or subcutaneous layer supports overall skin function, and loss or injury can impair wound healing, result in adhesions and/or contracture, and restrict soft-tissue mobility. Traditional wound management methods are often insufficient for hypodermal injuries, necessitating innovative approaches.

Recent Advances:

Hypodermal adipose-based solutions, including fat grafting and stem cell therapies, show promise for reconstruction. Fat grafting enhances soft-tissue bulk and contour, enhances mechanical properties, and promotes angiogenesis, offering versatility in addressing a range of wound scenarios, including challenging cases. Adipose-derived stem cells exhibit regenerative potential, modulate inflammation, and facilitate tissue repair, making them valuable for scar revision, skin rejuvenation, and managing chronic wounds. Acellular adipose derivatives, such as exosomes and liquid extracts, contain bioactive molecules that support tissue regeneration and collagen production. Adipose-derived acellular extracellular matrix holds promise in wound healing by enhancing cell behavior and angiogenesis.

Critical Issues:

In this review, we will discuss adipose-centered options for improvement of wound healing and for restoration of the hypodermis together as a cluster of efficient and cost-effective wound management in cases of complex soft-tissue injuries.

Future Directions:

These innovative therapies, while requiring further research, hold significant potential to simplify procedures, reduce costs, and improve the quality of life for patients facing challenging wounds.

Graphical Abstract

J. Peter Rubin, MD, MBA, FACS

Keywords

hypodermis wound care reconstruction adipose fat

INTRODUCTION

Scope

In wound healing and reconstruction, focus often centers on restoring the epidermis and dermis to reestablish the skin’s barrier, yet the underlying hypodermis is equally vital as the interface between superficial layers and deeper body structures. This review examines hypodermal structure and function, the impact of its injury, and current or emerging strategies for its use and restoration.

Translational relevance

In addition to fat grafting for hypodermal restoration, adipose-derived stem cell (ASC) therapies can augment hypodermal function. These approaches improve scar quality, skin appearance, and healing of chronic wounds, ulcers, and burns. Acellular adipose derivatives, such as exosomes and liquid extracts, deliver bioactive molecules that promote regeneration, angiogenesis, and collagen synthesis, offering stability, dosage precision, and low risk of adverse effects. Emerging adipose-derived acellular extracellular matrix (ECM) therapies further support healing by facilitating cellular processes, though continued research is needed to optimize their use.

Clinical relevance

Traditional wound management often fails to address hypodermal injuries. Microsurgical flaps are effective but costly, and skin grafts carry complications. Adipose-based therapeutics provide a valuable adjunct for soft tissue restoration, enhancing coverage and improving mechanical and cellular repair. This approach represents a paradigm shift in wound care—offering better outcomes, lower costs, and improved patient quality of life.

STRUCTURE AND FUNCTION OF THE HYPODERMIS

Hypodermal architecture

Deep to the dermis lies the hypodermal or subcutaneous plane (Fig. 1A). Though often used interchangeably with subcutaneous adipose, the term “hypodermis” encompasses a more complex structure and function. Globally, it consists of loose connective tissue enriched with adipose—the most variable integumentary layer—ranging from a minimal areolar plane to a thick adipofascial network.^1,2 In adipose-rich regions, connective fibers surround and invest adipose lobules,^2,3 while horizontal fibers of the superficial fascial system stabilize these layers and resist deformation across anatomical zones.^2,4,5 Stiffer vertical fibers anchor the dermis to deep fascia, transmitting force and motion through the hypodermis.^2,5,6 In mobile areas, a “microvacuolar” layer forms as polyhedral vacuoles appear and collapse with tissue movement.² Collagen- and elastin-rich sheets containing hyaluronic acid confer compliance and viscoelasticity.^7–9 This mobility supports interstitial fluid storage and homeostasis.^2,10 The hypodermis’ strength, elasticity, and deformability aid the skin’s barrier function by redistributing mechanical stress, a role linked to the relative resistance of hypodermal fibroblasts to fibrogenic transformation.^11,12

Figure 1.

(A) Schematic demonstrating the trilaminar integument and general composition of the hypodermis with demonstration of wound depths. (B) Predicted outcomes of untreated wounds by depth.

Functions of the hypodermis

Physical structure alone does not define hypodermal function. This layer contains intricate neurovascular and lymphovascular networks essential for thermoregulation and wound healing.^2,13–17 Hypodermal adipose also serves as a major metabolic reservoir with autocrine, paracrine, and immunological activity.¹⁷ Beyond mechanics, the hypodermis hosts diverse bioactive cell populations that sustain both local and adjacent tissue health.^18–20 ASCs and supporting cells endow it with regenerative, angiogenic, and immunomodulatory capacity.^18–20 Within its loose connective tissue and fascial planes, stromal cells reside in a matrix rich in glycosaminoglycans, proteoglycans, and water.²¹ These include adipocytes, preadipocytes, fibroblasts, pericytes, endothelial and sensory cells, and immune cells such as dendritic cells, macrophages, mast cells, and lymphocytes.^22–24 When enzymatically isolated, these form the heterogeneous stromal vascular fraction (SVF), a key component studied alongside ASCs for therapeutic potential.^18–22

HYPODERMAL INJURY, ADHESIONS, AND WOUND HEALING

Injuries affecting the hypodermis

Hypodermal trauma may result from external injuries penetrating the epidermis and dermis (burns, lacerations, penetrating trauma) or from deep-to-superficial mechanisms (pressure ulcers, hematomas, Morel-Lavallée lesions, iatrogenic oncologic extirpation) (Fig. 1B).^25–27 Full-thickness wounds inherently involve hypodermal damage. Numerous pathological conditions also affect this layer, including infections, vascular and autoimmune lesions, scleroderma, and lipodystrophies.^27–30 Age and nutrition further influence hypodermal integrity, as seen in deficits from anorexia and cachexia.^31–33 Because hypodermal thickness varies by anatomy and body habitus, injury effects differ by site (Fig. 1C). Two main considerations arise: (1) structural loss of subcutaneous tissue and (2) disruption of hypodermal support for epidermal and dermal homeostasis.

Consequences of hypodermal deficiency

When intact, the hypodermis cushions and separates the dermis from deeper structures while transmitting and redistributing mechanical force. Loss of this layer disrupts that interface.^34–36 Beyond reduced cushioning, it eliminates a mobile, deformable plane that enables tissue glide. Compared with adipose-rich hypodermis, the dermis is relatively inflexible.² Without the hypodermis, inelastic cicatrix can directly adhere to deeper and surrounding structures during healing, causing adhesions and contractures. This leads to morbidity—limited motion, functional loss, or poor cosmesis—especially across joints or facial muscles (Fig. 1B).^34–36 Deficiency also compromises redistribution of mechanical stress, predisposing skin and scar to reinjury,^34–39 and alters normal contour, creating cosmetic deformities.^38,39

Hypodermal injury and wound healing

Loss of the hypodermis removes key support systems for wound healing: (1) neurovascular and lymphovascular networks; (2) the hypodermal cellular niche, including SVF and ASCs; and (3) interstitial flow.² The impact depends on injury extent and collateral damage. Vascular, lymphatic, and neural elements traversing the hypodermis are lost, and while dermal vascular plexuses may sustain small wounds, extensive injury disrupts collateral flow.⁴⁰ ASCs also play roles in dermal and epidermal homeostasis.^31,41 Hypodermal loss additionally directly alters hemostasis, inflammation, proliferation, and maturation. Adipose-derived plasminogen activator inhibitor-1 stabilizes fibrin and inhibits fibrinolysis.⁴² Leptin enhances, while adiponectin inhibits, platelet aggregation.⁴² Adipocyte injury increases lipolysis and releases free fatty acids, attracting macrophages through GPR84 signaling to intensify inflammation.⁴³ Meanwhile, adipose-resident immune and stromal cells regulate inflammation through adipokines and reactive adipogenesis.⁴³ ASCs further modulate the inflammatory-to-proliferative transition and contribute to angiogenesis with pericytes and endothelial cells.⁴³ During remodeling, adipose regulates matrix turnover through metalloproteinases, while adiponectin limits fibrosis by suppressing TGF-β and CTGF.⁴³

APPROACH AND CONSIDERATIONS IN RESTORATION OF THE HYPODERMIS

Before reconstruction, safe and effective wound management takes priority. Multimodal care often involves debridement, infection control, moisture balance, and inflammation management.⁴⁴ Unlike superficial skin layers, the hypodermis lacks an effective moisture barrier and is highly vulnerable when exposed.⁴⁵ Thus, hypodermal reconstruction depends first on restoring cutaneous integrity. Once stable, both form and function of the hypodermis must be addressed, as it serves physical/mechanical and cellular/bioactive roles in skin physiology and repair. Reconstruction should therefore include: (1) rapid restoration of the skin barrier; (2) reduced cicatrix formation; (3) optimization of strength and function; (4) treatment of contour deformity; (5) mitigation of adhesion and contracture; and (6) restoration of soft padding. Some techniques, including primary closure, tissue rearrangement, and pedicled or free tissue transfer, may address these simultaneously. Microsurgical flap procedures remain the gold standard for soft-tissue reconstruction; however, they are resource-intensive, require specialized skills, and depend on viable donor sites, which may be limited in polytrauma cases.^46,47 Less intricate solutions, such as skin grafts or staged reconstructions, introduce other challenges.^48,49 Split-thickness grafts yield fragile coverage prone to trauma, contracture, and adhesion, while failing to restore hypodermal volume or contour. Full-thickness grafts improve outcomes but are restricted by donor availability and may still cause irregularities.^48,49 Approaches that restore hypodermal structure or function are therefore valuable adjuncts. As Dr. Ralph Millard’s principle of “like with like” suggests, autologous adipose—given its cellular, structural, and biochemical compatibility—is ideally suited for hypodermal reconstruction.^46,47 Fat is best used to repair fat, and growing evidence supports adipose-based therapies across wound care, reconstruction, and aesthetic surgery (Fig. 2).

Figure 2.

Schematic demonstrating the processing of whole adipose into a range of adipose-derived cellular and acellular therapeutics. Whole adipose collected by liposuction (lipoaspirate) is typically processed minimally to separate the desired tissue from any residual fluid or debris. Lipoaspirate may be used immediately as a fat graft or may be further processed. Chemical or enzymatic dissociation can be utilized to directly release resident cell populations. Mechanical dissociation provides and alternate enzyme-free strategy, which can produce a fractionated compound such as nanofat. Nanofat can be further processed resulting in complete disruption of all cellular components from which adipose extract or soluble extracellular matrix could be harvested. Both nanofat and SVF can be used to produce exosomes and conditioned media. Any of the more processed adipose-derived products could additionally be added back into lipoaspirate in a process called enrichment which is hypothesized to change the properties of the grafted fat. SVF, stromal vascular fraction.

LIKE-FOR-LIKE: ADIPOSE-BASED RECONSTRUCTION OF THE HYPODERMIS

Fat grafting

En bloc engraftment

Autologous adipose transplantation varies in technique, complexity, and volume. For small-volume grafting in well-vascularized sites, en bloc methods involve direct transfer of dissected adipose into a surgical pocket without liposuction or mechanical processing. Individual adipose pearls, small strips, and dermal-fat composite grafts have all been used.^50–53 More recently, skin-fat composite grafts combining full-thickness skin with 1–4 mm of fat have been described.⁵³ These grafts, lacking intrinsic blood supply, are limited by volume-to-surface ratio and recipient site revascularization capacity. However, their preserved internal connective architecture enhances structural stability. Dermal-fat grafts leverage dermal stiffness for contour correction, while skin-fat composites enable single-stage trilaminar reconstruction without microsurgery.⁵³

Engraftment of lipoaspirate

The now classical approach for hypodermal deficiency, popularized by Dr. Sydney Coleman, uses fat grafts harvested through liposuction (lipoaspirate).^54–56 Fat grafting augments soft-tissue volume and supports wound repair, particularly in extremity trauma with exposed tendons, bone, or neurovascular elements.^57,58 It provides immediate bulk, closes defects, and improves contour.^59–61 Fat grafts stimulate angiogenic remodeling, promoting oxygenation, nutrient delivery, and healing.⁶² This technique can be effective even in infected, contaminated, or poorly vascularized wounds such as diabetic foot ulcers, irradiated skin, osteoradionecrosis areas, and burn scars.^63–70 Successful engraftment requires meticulous technique to preserve adipocyte viability and prevent resorption.^61,71,72 Low-pressure aspiration with wide-bore cannulas minimizes trauma, and gentle processing isolates viable tissue.^61,71,72 Small aliquots injected into vascular beds better neovascularize and avoid central necrosis.^61,71,72 Site-specific methods vary—facial grafts require small, uniform deposits to prevent nodularity, while larger areas (e.g., breast, buttocks) demand layered placement to avoid resorption and contour irregularities.⁷³ Adherence to atraumatic injection pressure, sterile technique, and proper graft volume enhances survival and long-term retention.^61,71–73

Use of nanofat (and other mechanically processed preparations)

Not all fat grafts are structural (i.e., dependent on the architecture of the fat graft). During liposuction and postprocessing of fat, the physical structure of adipose can be progressively fractionated, resulting in a preparation which maintains portions of the cellular milieu without maintaining the physical structure of each adipose lobule. Nanofat, described by Tonnard et al. in 2013, is produced by serial emulsification, lysing adipocytes but retaining regenerative cells.⁷⁴ Fractionated fat preparations have been proposed as treatment for scar revision and skin rejuvenation.^75–79 By introducing these fat preparations into scar tissue through injections or topical application, it is possible to ameliorate scar texture, reduce scar thickness, and restore a more natural appearance to the skin.^75–79 Furthermore, akin to whole-fat grafts, the safety profile of these fat preparations is favorable. These autologous are enzyme-free and integrate naturally with the surrounding tissue. Minimal downtime and favorable biocompatibility make them promising tools for regenerative and aesthetic applications.^77,78 Consequently, these advancements hold substantial promise for the future of regenerative medicine and aesthetic surgery.

Topically applied fat

Fat only preparations

Topical fat preparations are a recent addition to clinical practice, used selectively alongside traditional fat transfer. Dr. Nelson Piccolo and others advocate their use for superficial degloving injuries, applying lipoaspirate both topically and through injection to optimize wound beds for healing and later grafting.^80,81 Lipoaspirate has also been used with platelet-rich plasma to promote epithelialization.⁸² In aesthetics, Dr. Stephen Cohen describes combining nanofat with microneedling to bypass the epidermal barrier for skin rejuvenation.⁸³ Nanofat is highly mechanically fractionated, resulting in adipocyte lysis with retention of other cellular components of the SVF.⁷⁴ This results in relative enrichment of bioactive constituents such as growth factors, cytokines, and ASCs. Nanofat, as a topical preparation, is ascribed similar properties to when injected, most notably improvements in overall skin quality and healing.^75–79

Adipose-based reconstruction

Capitalizing on the above clinical experiences, our group is evaluating adipose-based reconstruction as a scaffold for immediate skin grafting. This approach offers biological soft-tissue coverage with minimal donor burden, reducing surgical complexity and eliminating the need for microsurgery. Grafted adipose demonstrates viability in poorly vascularized wound beds and over critical structures such as nerves, tendons, and vessels.^57,58 In certain circumstances, fat grafting can be compatible around osseous injuries and orthopedic hardware, broadening its applicability.^58,84 Fat grafts applied to the wound base can integrate and granulate, which supports the potential for adipose as a first layer to support subsequent skin grafting.⁸² The presence of fat additionally could then be hypothesized to act as a physical barrier between a delayed skin graft and the wound base. In summary, while still in development, this technique presents a promising avenue for wound reconstruction, offering immediate coverage, adaptability across indications, and improved healing while simplifying care.

Adipose-stem cell-based therapies

ASCs have garnered substantial attention in recent years, primarily owing to their regenerative properties and exceptional versatility in addressing a wide spectrum of medical conditions.^85–89 These multipotent cells, sourced from adipose tissue, have paved the way for innovative therapeutic approaches capable of addressing a myriad of medical conditions. ASCs are distinguished by their remarkable regenerative potential, characterized by their ability to differentiate into various cell lineages, encompassing adipocytes, osteocytes, chondrocytes, and myocytes.^85–89 Their regenerative prowess emanates from the secretion of growth factors, cytokines, and extracellular vesicles, which assume pivotal roles in facilitating tissue repair and modulating the local microenvironment.^90,91 Furthermore, ASCs exhibit immunomodulatory effects, exerting control over inflammatory responses.⁹² ASCs have demonstrated efficacy when injected into scar and skin, for wound healing and repair, and in the setting of nonhealing or chronic wounds, ulcers, and burns.

Allogeneic options

While what has been described above specifically refers to the use of autologous tissues, allogeneic transplantation has been described.^93–96 Unlike autologous tissue, allogeneic cells are genetically dissimilar between host and recipient. This presents unique concerns regarding histocompatibility and immunological activation not found in autologous transfer. While adipose does have immunomodulatory potential (discussed below), allogeneic adipose contains donor-specific antigenic determinants capable of eliciting robust T-cell-mediated and antibody-mediated immune responses further, the presence of immunological populations within adipose may present an opportunity for graft versus host response.^97–99 Despite this, allogeneic tissue sources offer the potential for the collection, expansion, and administration of cells without the need for additional autologous harvest. Allogeneic studies are more common in animals, where control of the host immune system is more easily achieved; however, feasibility and safety studies of allogeneic stem cell transfer are underway.^{93–96,100,101} Interestingly, allogeneic fat grafting, specifically fat grafting from cadaveric sources, has historic precedent, though it is not generally used in clinical practice.⁹⁶ One of the proposed mechanisms for fat engraftment, the Host Cell Replacement Theory, postulates that a majority, if not all, of the grafted cells die and are replaced by recipient cells, which recellularize the transplanted adipose matrix.¹⁰² This is proposed as a potential hypothesis for the historical viability of cadaveric fat. Alternatively, ASCs, SVF, and their secretome have shown promise in enhancing graft survival and functional integration in composite tissues.⁴³ ASCs have a native immunomodulatory effect on macrophages and through secretion of IL-10, TGF-β, and prostaglandin E₂, and direct cell contact. Furthermore, ASCs have demonstrated potential to suppress effector T and B cell proliferation, impair NK cell function and dendritic cell maturation, and promote regulatory immune cell populations, including Tregs, Bregs.^43,97,98

Acellular adipose-derived therapeutics

Adipose is a complex tissue, and as its properties are better understood strategies that make use of adipose tissue are better refined. A more recent area of discovery focuses on acellular derivatives of adipose—exosomes, liquid extracts, and ECM being some of the more well-described (Fig. 2).

Exosomes

Exosomes are a class of extracellular organelle used in intercellular communication, which have been implicated in the efficiency of stem cell therapy.¹⁰³ Each exosome is a membrane-bound vesicle, secreted from intracellular multivesicular bodies, which can carry a wide range of cargo between cells.¹⁰³ The exact role of exosomes in skin homeostasis is an active area of inquiry, and exosome-mediated signals have a role in wound healing, immune regulation and inflammation, angiogenesis, proliferation, and reepithelialization of keratinocytes, and collagen regulation during scar formation.^103–107 Adipose-derived exosomes are enriched with bioactive molecules, such as growth factors, cytokines, and microRNAs, which play pivotal roles in cell signaling and tissue repair.^103–107 Given this wide range of exosome-mediated functions, exosomes are being evaluated for therapeutic application. There are logistic benefits to exosome-based therapy when compared with fat or cell transfer: (1) as exosomes can be released stably into the extracellular environment, they can be repeatedly collected from both in vivo and in vitro sources without destruction of the cells involved in production; (2) exosomes can be stored stably by freezing or lyophilization; (3) different exosomes can be released in response to distinct cell stimuli; (4) exosomes are acellular and are both (a) not dependent on viability of engraftment for function and (b) may be collected from allogeneic sources; and (5) exosomes may be administered in a dose-dependent manner.^103–109

Exosome therapy is still a developing field, and best practices for the administration of exosomes are still being developed. Precise targeting of exosomes to specific recipient cells of interest is challenging. When applied topically to uninjured skin, epidermal penetration occurs in a time-dependent manner.¹¹⁰ This can be facilitated clinically by techniques that bypass or disrupt the epidermal barrier, such as microneedling.¹¹¹ The function of exosomes is affected by their contents and reflects both their cell of origin and the signal that initially stimulated exosome secretion.¹¹² ASC-derived exosomes have consequently demonstrated several properties similar to those ascribed to ASCs, including anti-inflammatory and immunoregulatory properties, pro-angiogenic signaling, and stimulation of ECM remodeling.^104,105 Exosomes are additionally being evaluated as a potential adjunct to fat grafting by improving graft retention.¹⁰⁶ Exosomes offer a potential acellular option for hostile wound environments, such as the chronic diabetic wounds, where preclinical studies have demonstrated wound closure by stimulating angiogenesis, fibroblast activity, and collagen synthesis.¹⁰⁷

Adipose liquid extracts/emulsions

Exosomes are only a single component of the bioactive milieu of adipose, which include hormonal regulators such as adiponectin and leptin as well as a host of unencapsulated cytokines. Alternate cell-free strategies have also been described, including conditioned medium and liquid/tissue extracts.^113–116 Unlike conditioned media, which possess logistical challenges in human use, adipose liquid/tissue extracts are cell-free fluid extracted from adipose tissue through physical methods. These extracts have demonstrated preclinical versatility in various applications, including wound healing, where they promotes neovascularization and accelerates the healing process by stimulating cell proliferation and migration.^116,117 In addition, adipose liquid extracts have demonstrated limited improvement of tissue ischemia through upregulation of angiogenesis.^116,117 The exact immunological consequences of these extracts are still being studied; however, further research is needed to standardize protocols and maximize therapeutic efficacy in clinical applications.

Adipose-derived acellular ECM

The ECM of human skin includes both fibrous proteins (collagens, elastin, and fibronectin) and proteoglycans and glycosaminoglycans. This protein matrix is crucial for normal cell behavior, primarily mediated by integrins, impacting cell proliferation, differentiation, and apoptosis. It further modulates the activity of growth factors and cytokines, protecting them from degradation and controlling their release. In normal wound healing matrix metalloproteinases and tissue inhibitors of metalloproteinases maintain ECM homeostasis throughout phases of hemostasis, inflammation, proliferation, and remodeling.^118,119 Disruption of these processes in chronic and complex wounds results in prolonged inflammation and impaired transition to the proliferation and remodeling phases.^118,119 This dysregulation further affects collagen synthesis, proteolytic enzyme activity, and the balance between ECM synthesis and degradation, leading to dysfunctional ECM that hinders proper wound healing.^118,119 Adipose tissue and ASCs are potent producers of ECM, and acellular ECM is an alternative approach to cell-based wound therapy under current investigation.^120–122 Decellularized ECM scaffolds derived from allogeneic human skin or animal tissues have been utilized to provide topical management of wounds; however, these products face challenges, including sustained inflammation and incomplete healing due to ECM molecule integrity after decellularization, potential immune responses to xenogeneic ECM, and pathogen transfer risk exist.^120–124

DISCUSSION, CURRENT STATUS, AND OTHER CLINICAL CONSIDERATIONS

The hypodermis plays a multifaceted role in maintaining health and well-being, serving as a mechanical buffer, glide plane, and bioactive layer that maintains overall integumentary function. Loss of this layer leads to adhesions, contractures, and reduced mobility, especially near joints and facial muscles. Hypodermal tissues in wound reconstruction show promise for functional recovery. Fat grafting improves contour and pliability, intercalates scar tissue to restore motion, but requires precise handling to prevent ischemic injury to graft and resorption.^61,71,72 This concern can apply to injected lipoaspirate, topical fat, and composite grafts like dermal-fat constructs. Furthermore, topical applications rely on revascularization solely from the wound base, increasing vulnerability. Nonstructural cell sources such as SVF, ASCs, and nanofat predictably have a lower ischemic burden and stem cell-based therapies offer regenerative potential, modulate inflammation, and promote tissue repair. Their application has demonstrated efficacy in scar revision and burns.^125,126 Acellular adipose derivatives (e.g., exosomes, liquid extracts) deliver bioactive molecules promoting regeneration, angiogenesis, and collagen formation with improved stability, dosage precision, and allogeneic potential. Adipose-derived ECM likewise supports adhesion, migration, and angiogenesis. Though not dependent on vascularization, acellular products may introduce infection or embolic risks if improperly applied.

Furthermore, these techniques range a spectrum of regulatory and logistical concerns. In the United States, autologous adipose‐based therapies each occupy a distinct regulatory niche under U.S. Food and Drug Administration (FDA) guidance (Table 1).^125–129 Traditional “en bloc” and structural autologous fat grafts, transferred within a single operation with only minimal handling such as sizing or rinsing, qualify as minimally manipulated, homologous‐use tissues under Section 361 of the Public Health Service Act (21 CFR 1271) and are in widespread clinical use across multiple surgical specialties. Processing devices used for these grafts—centrifuges, filters, and comparable systems—are FDA Class II devices with 510(k) clearance, reflecting an established safety framework.^127–131 Topically applied adipose preparations or “topical lipoaspirate” remain investigational and context dependent; although potentially exempt under the same‐surgical‐procedure exception, attempts to leverage growth factors or stromal cells for healing may constitute non‐homologous use, reclassifying the product as a biological under Section 351. Similarly, mechanically processed emulsions such as nanofat and SVF occupy a legally and scientifically unsettled category. Following United States v. California Stem Cell Treatment Center (C.D. Cal. 2022; 9th Cir. 2024), the FDA retains oversight of SVF‐based interventions, which are presently considered more‐than‐minimally manipulated and investigational, without approved indications.^132–135 Allogeneic applications further diverge: whole‐fat grafts from cadaveric sources may fall under HCT/P tissue‐bank regulations with donor screening requirements but lack approved live‐cell product; some acellular derivatives including specific decellularized adipose ECM can qualify as Section 361 HCT/Ps for structural use, whereas cell‐derived exosomes or secretomes currently constitute Section 351 biologics requiring full premarket evaluation.^127–131

Table 1.

Current FDA status and clinical use of adipose and Adipose-Derived techniques

Fraction	Definition	FDA status	Routine clinical use
“En Bloc” Fat Engraftment (Fat Pearls, Strips, Composite Grafts)	The patient’s fat is removed and reimplanted in the same patient during one surgery without handling	Section 361* of the Public Health Service Act (21 CFR 1271)	Widespread, multiple specialties
	This qualifies as minimally manipulated, homologous-use tissue transfers	Section 361 (HCT/P): no IND or FDA premarket clearance needed	Widespread, multiple specialties
Structural Autologous Fat Grafts (Like-for-Like Reconstruction)	The patient’s fat is removed and reimplanted in the same patient during one surgery with only minor handling such as sizing, rinsing, or filtering	Section 361* of the Public Health Service Act (21 CFR 1271)	Widespread, multiple specialties
	These manipulations qualify as “minimally manipulated, homologous-use tissue transfers”	Section 361 (HCT/P): no IND or FDA premarket clearance needed	Widespread, multiple specialties
Devices used to process fat (centrifuges, filters, etc.)	Devices used to facilitate minimal manipulation of homologous tissues	510(k)-cleared for this purpose, underscoring that the practice is considered safe and permissible. Many processing devices are FDA Class II devices with 510(k) clearance for fat processing, however adipose tissue is not itself a separately approved “product.”	Widespread, multiple specialties
Topically Applied Adipose Preparations/Topical Lipoaspirate for Wound Coverage	Definition critical without preexisting accepted for widespread topical use of adipose There is no FDA-approved product or pathway. A) If leveraged as autologous use in the same surgery could invoke the same surgical procedure exception as above (Section 361 (HCT/P)) B) Consideration must be made toward language as use of fat aimed at leveraging its growth factors and cells to encourage healing may be considered nonhomologous which may change the definition to a biological treatment (see below for nonstructural autologous fat fractions)		Currently, this technique is done only on a case-by-case surgical judgment, not as a standardized approved therapy.
Nonstructural Autologous Fat Fractions and Adipose-Derived Cellular Therapies	Indeterminate/Pending: Mechanically, rather than enzymatically, processed adipose emulsions such as nanofat have been cited under the umbrella “same surgical procedure.” Currently, the stance of the FDA in this is that the use of fat-derived cells to achieve healing or skin improvements is not the same function that fat tissue serves in the body and can be considered more-than-minimally manipulated (the original tissue structure is substantially altered) or to be used for a new purpose, which places them under Section 351 (drug/biologic). Per July 2020 guidance by the U.S. Department of Health and Human Services “Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use” Structural tissues may be processed by various machining and other mechanical methods to change the size or shape of the HCT/P. Such processing can be either minimal manipulation or more than minimal manipulation depending on whether the processing alters the original relevant characteristics of the structural tissue relating to its utility for reconstruction, repair, or replacement. In United States v. California Stem Cell Treatment Center in 2021 status of SVF was held as a medical procedure exempt from FDA oversight. This was overturned by 9th Circuit appeals court in 2024 with FDA oversight granted. As of the writing of this review the Supreme Court has been petitioned to review the 9th Circuit’s decision.		As of 2025, no nanofat/SVF product has FDA approval for any indication, and such treatments are considered investigational use. There are several medical practitioners in the United States who provide these treatments, primarily aesthetic, plastic, and dermatologic practitioners.
Topical Nanofat for Skin Rejuvenation	Fat emulsions (nanofat) are sometimes applied with microneedling or injected intradermally to improve skin quality, often in aesthetic and regenerative or rejuvenative contexts.	Regulatory guidance is as above. Discussion ongoing in the setting where no injection or needling occurs as in a topical cosmetic or facial, however, guidance is ongoing.	Clinical Use as Above
Allogeneic Fat Grafts (Cadaveric Fat)	Indeterminate Were cadaveric or other allogeneic whole fat to be used, the potential use scenario would fall under banked human tissue (21 CFR 1271) as a nonhomologous, banked tissue requiring all donor testing and eligibility and may be considered under the broader category of human cells, tissues, or cellular or tissue-based products (HCT/Ps). Notably this has not been specifically legislated at this time and there is no FDA-approved banked fat graft product with live cells on the market.		Uncommon. Historical and Investigational Use.
Allogeneic Adipose Cell Products	Stem cells or SVF taken from donor fat and used in another person.	This is treated under Section 351 (drug/biological).	Investigational use.
Allogeneic Cell-Free (Acellular) Derivatives	Extracellular Matrix (ECM) from Donor Fat: Injectable allograft adipose matrices. These are made from donated human fat that’s processed to remove all cellular elements, leaving behind the collagen and protein scaffold.	Allogeneic Fat ECM scaffolds (decellularized)—361 HCT/P (tissue allograft). Yes, allowed as long as They are intended for structural (homologous) use.	Widespread Clinical Use
Allogeneic Cell-Free (Acellular) Derivatives	Exosomes and Microvesicles. Some labs extract exosomes (tiny vesicles containing signaling molecules) from cultured adipose-derived cells. Acellular Adipose Extracts (Liquid Emulsions/Secretome): These would be cell-free liquids derived from adipose tissue.	Allogeneic cell-derived factors (live or encapsulated)—351 Biologic. Not approved for routine use; require trials. No current FDA-approved indications	Investigational

FDA, Food and Drug Administration; SVF, stromal vascular fraction; ECM, extracellular matrix.

TAKE-HOME MESSAGES

The hypodermis or subcutaneous layer of the skin is crucial for skin health, acting as a barrier and supporting movement. Its loss in full-thickness injuries contributes to complications including adhesions and restricted mobility.

This hypodermal layer is additionally host to a complex cellular niche which can be damaged or dysregulated in hypodermal trauma. The consequences of disruption of this niche are an active area of inquiry.

Skin grafts, while effective in restoring the cutaneous barrier, do not directly address hypodermal deficiency. Alternative techniques including free or pedicled flap reconstruction which may address hypodermal deficiency have higher technical, logistical, and donor site barriers.

Adipose-directed therapies including autologous fat grafting more directly targets hypodermal deficiency.

Clinically, there are a range of autologous fat grating techniques which include en block fat transfer, dermal fat grafts, cannula-assisted lipografting, as well as more mechanically fractionated fat preparations including nanofat grafting. Each of these techniques has a different clinical role with distinct indications and limitations.

In addition, cellular preparation derived from adipose including ASCs, are being studied for potential efficacy in scar and skin rejuvenation and in the area of chronic wounds, ulcers, and burns.

Acellular derivatives of adipose tissue, such as exosomes and ECM, contain bioactive molecules for tissue regeneration. Stem cell-derived ECM supports wound healing but requires further research for clinical use.

CONCLUSION

In summary, the role and use of the hypodermis in wound healing is a crucial aspect of wound healing that has long been overlooked. Hypodermal injuries can lead to persistent challenges, including adhesions, contractures, and restricted mobility. Conventional wound management strategies may fall short in addressing these challenges. Adipose-based solutions, including fat grafting, stem cell therapies, and acellular derivatives, offer promising avenues for hypodermal reconstruction. These approaches provide immediate soft-tissue coverage, enhance angiogenesis, and improve mechanical properties, ultimately contributing to more efficient and effective wound healing. While these therapies are still in development and require further research, they hold the potential to simplify wound reconstruction procedures, reduce health care costs, and improve the quality of life for patients with complex soft-tissue injuries. The multifaceted role of adipose tissue in health and well-being continues to expand, offering new hope for those facing challenging wound scenarios.

AUTHORS’ CONTRIBUTIONS

S.J.L. and J.P.R.: Conceptualization (J.P.R.); methodology (equal); writing—original draft (S.J.L.); writing—review and editing (equal).

Footnotes

ACKNOWLEDGMENTS AND FUNDING SOURCES

No funding was received for this review.

AUTHOR DISCLOSURE AND GHOSTWRITING

No ghostwriters were utilized in generation of this article.

ABOUT THE AUTHORS

Shawn J. Loder, MD, is a resident surgeon with the Department of Plastic Surgery at the University of Pittsburgh. J. Peter Rubin, MD, MBA, FACS, holds multiple roles at the University of Pittsburgh, including Chair of the Department of Plastic Surgery, UPMC Endowed Professor of Plastic Surgery, and Director of UPMC Wound Healing Services. Rubin leads a research program focusing on adipose-derived stem cells and codirects the Adipose Stem Cell Center at the university. He serves as the principal investigator for an NIH-funded project dedicated to developing cell-based techniques for soft tissue reconstruction postcancer therapy. In addition, he conducts research on soft tissue reconstruction for injured military personnel with the Department of Defense Armed Forces Institute for Regenerative Medicine (AFIRM).

Abbreviations and Acronyms

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