Wounds

Regenerative medicine encompasses innovative therapies that allow the body to repair or regenerate aging cells, tissues, and organs. The skin is a particularly attractive organ for the application of novel regenerative therapies due to its easy accessibility. Among these therapies, stem cells and platelet-rich plasma (PRP) have garnered interest based on their therapeutic potential in scar reduction, antiaging effects, and treatment of alopecia.

Stem cells possess the cardinal features of self-renewal and plasticity. Self-renewal refers to symmetric cell division generating daughter cells identical to the parent cell.¹ Plasticity is the ability to generate cell types other than the germ line or tissue lineage from which stem cells derive.² Stem cells can be categorized according to their differentiation potential. Totipotent stem cells may develop into any primary germ cell layer (ectoderm, mesoderm, endoderm) of the embryo, as well as extraembryonic tissue such as the trophoblast, which gives rise to the placenta. Pluripotent stem cells such as embryonic stem cells have the capacity to differentiate into any derivative of the 3 germ cell layers but have lost their ability to differentiate into the trophoblast.³ Adults lack totipotent or pluripotent cells; they have multipotent or unipotent cells. Multipotent stem cells are able to differentiate into multiple cell types from similar lineages; mesenchymal stem cells (MSCs), for example, can differentiate into adipogenic, osteogenic, chondrogenic, and myogenic cells.⁴ Unipotent stem cells have the lowest differentiation potential and can only self-regenerate. Herein, we review stem cell sources and their therapeutic potential in aesthetic dermatology.

Multipotent Stem Cells

Multipotent stem cells derived from the bone marrow, umbilical cord, adipose tissue, dermis, or hair follicle bulge have various clinical applications in dermatology. Stem cells from these sources are primarily utilized in an autologous manner in which they are processed outside the body and reintroduced into the donor. Autologous multipotent hematopoietic bone marrow cells were first successfully used for the treatment of chronic wounds and show promise for the treatment of atrophic scars.^5,6 However, due to the invasive nature of extracting bone marrow stem cells and their declining number with age, other sources of multipotent stem cells have fallen into favor.

Umbilical cord blood is a source of multipotent hematopoietic stem cells for which surgical intervention is not necessary because they are retrieved after umbilical cord clamping.⁷ Advantages of sourcing stem cells from umbilical cord blood includes high regenerative power compared to a newborn’s skin and low immunogenicity given that the newborn is immunologically immature.⁸

Another popular source for autologous stem cells is adipose tissue due to its ease of accessibility and relative abundance. Given that adipose tissue–derived stem cells (ASCs) are capable of differentiating into adipocytes that help maintain volume over time, they are being used for midface contouring, lip augmentation, facial rejuvenation, facial scarring, lipodystrophy, penile girth enhancement, and vaginal augmentation. Adipose tissue–derived stem cells also are capable of differentiating into other types of tissue, including cartilage and bone. Thus, they have been successfully harnessed in the treatment of patients affected by systemic sclerosis and Parry-Romberg syndrome as well in the functional and aesthetic reconstruction of various military combat–related deformities.^9,10

Adipose tissue–derived stem cells are commonly harvested from lipoaspirate of the abdomen and are combined with supportive mechanical scaffolds such as hydrogels. Lipoaspirate itself can serve as a scaffold for ASCs. Accordingly, ASCs also are being utilized as a scaffold for autologous fat transfer procedures in an effort to increase the viability of transplanted donor tissue, a process known as cell-assisted lipotransfer (CAL). In CAL, a fraction of the aspirated fat is processed for isolation of ASCs, which are then recombined with the remainder of the aspirated fat prior to grafting.¹¹ However, there is conflicting evidence as to whether CAL leads to improved graft success relative to conventional autologous fat transfer.^12,13

The skin also serves as an easily accessible and abundant autologous source of stem cells. A subtype of dermal fibroblasts has been proven to have multipotent potential.^14,15 These dermal fibroblasts are harvested from one area of the skin using punch biopsy and are processed and reinjected into another desired area of the skin.¹⁶ Autologous human fibroblasts have proven to be effective for the treatment of wrinkles, rhytides, and acne scars.¹⁷ In June 2011, the US Food and Drug Administration approved azficel-T, an autologous cellular product created by harvesting fibroblasts from a patient’s own postauricular skin, culture-expanding them in vitro for 3 months, and reinjecting the cells into the desired area of dermis in a series of treatments. This product was the first personalized cell therapy approved by the US Food and Drug Administration for aesthetic uses, specifically for the improvement of nasolabial fold wrinkles.¹⁸

In adults, hair follicles contain an area known as the bulge, which is a site rich in epithelial and melanocytic stem cells. Bulge stem cells have the ability to reproduce the interfollicular epidermis, hair follicle structures, and sebaceous glands, and they have been used to construct entirely new hair follicles in an artificial in vivo system.¹⁹ Sugiyama-Nakagiri et al²⁰ demonstrated that an entire hair follicle epithelium and interfollicular epidermis can be regenerated using cultured bulge stem cells. The cultured bulge stem cells were mixed with dermal papilla cells from neonatal rat vibrissae and engrafted into a silicone chamber implanted on the backs of severe combined immune deficient (SCID) mice. The grafts exhibited tufts of hair as well as a complete interfollicular epidermis at 4 weeks after transplantation.²⁰ Thus, these bulge stem cells have the potential to treat male androgenic alopecia and female pattern hair loss. Bulge stem cells also have been shown to accelerate wound healing.²¹ Additionally, autologous melanocytic stem cells located at the hair follicle bulge are effective for treating vitiligo and are being investigated for the treatment of hair graying.²²

Induced Pluripotent Stem Cells

Given the ethical concerns that surround the procurement and use of embryonic stem cells, efforts have been made to retrieve pluripotent stem cells from adults. A major breakthrough occurred in 2006 when researchers altered the genes of specialized adult mouse cells to cause dedifferentiation and the return to an embryoniclike stem cell state.²³ Mouse somatic cells were reprogrammed through the activation of a combination of transcription factors. The resulting cells were termed induced pluripotent stem cells (iPSCs) and have since been recreated in human cell lines. The discovery of iPSCs precipitated a translational science revolution. Physician-scientists sought ways to apply the reprogrammed cells to the pathophysiology of obscure diseases, examination of drug targets, and regeneration of human tissue.²⁴ Tissue regeneration via induced naïve somatic cells has shown promise as a future method to treat neurologic, cardiovascular, and ophthalmologic diseases.²⁵

As the technology of cultivating and identifying optimal sources of iPSCs continues to advance, stem cell–based treatments have evolved as leading prospects in the field of biogerontology.^26-29 Although much of the research in antiaging medicine has utilized iPSCs to reprogram cell senescence, the altering of iPSCs at a cellular level also allows for the stimulation of collagen synthesis. This potential for collagen generation may have direct applicability in dermatologic practice, particularly for aesthetic treatments.

Much of the research into iPSC-derived collagen has focused on genodermatoses. Itoh et al³⁰ examined the creation of collagen through iPSCs to identify possible treatments for recessive dystrophic epidermolysis bullosa (DEB). Recessive DEB is characterized by mutations in the COL7A1 gene, which encodes type VII collagen, a basement membrane protein and component of the anchoring fibrils essential for skin integrity.³¹ Itoh et al³⁰ began with source cells obtained from a skin biopsy. The cells were dedifferentiated to iPSCs and then induced into dermal fibroblasts according to the methods established in prior studies of embryonic stem cells, namely with the use of ascorbic acid and transforming growth factor b. The newly formed fibroblasts were determined to be functional based on their ability to synthesize mature type VII collagen.³⁰ Once the viability of the iPSC-derived fibroblasts was confirmed in vitro, the cells were further tested through combination with human keratinocytes on SCID mice. The human keratinocytes grew together with the iPSC-derived fibroblasts, producing type VII collagen in the basement membrane zone and creating an epidermis with the normal markers.³⁰ Similarly, Robbins et al³² utilized SCID mice to successfully demonstrate that the transfection of keratinocytes from patients with junctional epidermolysis bullosa into SCID mice produced phenotypically normal skin.

Sebastiano et al³³ combined the concepts of iPSCs and genome editing in another study of recessive DEB. The investigators first cultured iPSCs from biopsies of affected patients. After deriving iPSCs and correcting their mutation via adenovirus-associated viral gene editing, the COL7A1 mutation-free cells were differentiated into keratinocytes. These iPSC-derived keratinocytes were subsequently grafted onto mice, which led to the production of wild-type collagen VII and a stratified epidermis. Despite this successful outcome, the grafts of iPSC-derived epidermis did not survive longer than 1 month.³³

One of the many obstacles facing the practical use of stem cells is their successful incorporation into human tissue. A possible solution was uncovered by Zhang et al³⁴ who examined iPSC-derived MSCs. Mesenchymal stem cells communicate via paracrine mechanisms, whereby exosomes containing RNA and proteins are released to potentiate a regenerative effect.³⁵ Zhang et al³⁴ found that injecting exosomes from human iPSC-derived MSCs into the wound sites of rats stimulated the production of type I collagen, type III collagen, and elastin. The wound sites demonstrated accelerated closure, narrower scar widths, and increased collagen maturity.

Understanding the role that local environment plays in stem cell differentiation, Xu et al³⁶ aimed to create an extracellular scaffold to induce fibroblast behavior from iPSCs. The authors engineered a framework similar to the normal extracellular membrane using proteoglycans, glycosaminoglycans, fibrinogen, and connective tissue growth factor. The iPSCs were then applied to the scaffolding, which led to successful fibroblast differentiation and type I collagen synthesis.³⁶ This use of local biosignaling cues holds important ramifications for controlling the fate of stem cells that have been introduced into a new environment.

Although the application of iPSCs in clinical dermatology has yet to be achieved, progress in the field is moving at a rapid pace. Several logistical elements require further mastery before therapeutics can be delivered. These areas include the optimal environment for iPSC differentiation, methods for maximization of graft survival, and different modes of transplanting iPSC-derived cells into patients. In cosmetic practice, success will depend on intradermal injections of collagen-producing iPSC-derived cells that possess long-term proliferative potential. Current research in mice models has demonstrated viability up to 16 weeks after intradermal injection of such cells.³⁷

Plant Stem Cells

In discussing the dermatologic applications of stem cell technology, clinicians should be aware of the plant stem cell products that have become a popular cosmeceutical trend. Companies advertise plant cells as a natural source of regenerative cells that can induce rejuvenation in human skin; however, there are no significant data to indicate that plant stem cells encourage or activate cellular growth in humans. Indeed, for stem cells to differentiate and produce viable components, the cells must first be incorporated as living components in the host tissue. Because plant stem cells do not survive in human tissue and plant cell cytokines fail to interact with the receptors on human cells, their current value in cosmeceuticals may be overstated.

Platelet-Rich Plasma

Platelet-rich plasma also is commonly associated with stem cell therapy, as PRP is known to potentiate stem cell proliferation, migration, and differentiation. However, PRP does not contain stem cells and is instead autologous plasma concentrated with platelets. In fact, platelets cannot even be classified as cells given that they lack a nucleus; platelets are considered cell fragments. The regenerative potential of PRP can be attributed to the growth factors released from platelets, which play an important role in tissue regeneration and repair. Platelet-rich plasma currently is being used in dermatology for skin rejuvenation (reduction of wrinkles and furrows) and treatment of acne scars.³⁸ There also is evidence supporting the effectiveness of PRP for alopecia and wound therapy, as growth factors play a vital role in hair growth and wound healing.³⁸ Apart from the use of PRP on its own, it can be used as a supplement to enhance the effects of antiaging procedures such as microneedling.³⁹

Future Directions

Multipotent stem cells and iPSCs discussed herein provide much promise in the field of regenerative dermatology. They are increasingly accessible and circumvent the use of ethically questionable embryonic stem cells. Although there is a general consensus on the great potential of stem cells for treating aesthetic skin conditions, high-quality randomized controlled trials remain scarce within the literature. Recognizing and optimizing these opportunities remains the next step in the future delivery of evidence-based care in regenerative dermatology.

Regenerative medicine encompasses innovative therapies that allow the body to repair or regenerate aging cells, tissues, and organs. The skin is a particularly attractive organ for the application of novel regenerative therapies due to its easy accessibility. Among these therapies, stem cells and platelet-rich plasma (PRP) have garnered interest based on their therapeutic potential in scar reduction, antiaging effects, and treatment of alopecia.

Stem cells possess the cardinal features of self-renewal and plasticity. Self-renewal refers to symmetric cell division generating daughter cells identical to the parent cell.¹ Plasticity is the ability to generate cell types other than the germ line or tissue lineage from which stem cells derive.² Stem cells can be categorized according to their differentiation potential. Totipotent stem cells may develop into any primary germ cell layer (ectoderm, mesoderm, endoderm) of the embryo, as well as extraembryonic tissue such as the trophoblast, which gives rise to the placenta. Pluripotent stem cells such as embryonic stem cells have the capacity to differentiate into any derivative of the 3 germ cell layers but have lost their ability to differentiate into the trophoblast.³ Adults lack totipotent or pluripotent cells; they have multipotent or unipotent cells. Multipotent stem cells are able to differentiate into multiple cell types from similar lineages; mesenchymal stem cells (MSCs), for example, can differentiate into adipogenic, osteogenic, chondrogenic, and myogenic cells.⁴ Unipotent stem cells have the lowest differentiation potential and can only self-regenerate. Herein, we review stem cell sources and their therapeutic potential in aesthetic dermatology.

Multipotent Stem Cells

Multipotent stem cells derived from the bone marrow, umbilical cord, adipose tissue, dermis, or hair follicle bulge have various clinical applications in dermatology. Stem cells from these sources are primarily utilized in an autologous manner in which they are processed outside the body and reintroduced into the donor. Autologous multipotent hematopoietic bone marrow cells were first successfully used for the treatment of chronic wounds and show promise for the treatment of atrophic scars.^5,6 However, due to the invasive nature of extracting bone marrow stem cells and their declining number with age, other sources of multipotent stem cells have fallen into favor.

Umbilical cord blood is a source of multipotent hematopoietic stem cells for which surgical intervention is not necessary because they are retrieved after umbilical cord clamping.⁷ Advantages of sourcing stem cells from umbilical cord blood includes high regenerative power compared to a newborn’s skin and low immunogenicity given that the newborn is immunologically immature.⁸

Another popular source for autologous stem cells is adipose tissue due to its ease of accessibility and relative abundance. Given that adipose tissue–derived stem cells (ASCs) are capable of differentiating into adipocytes that help maintain volume over time, they are being used for midface contouring, lip augmentation, facial rejuvenation, facial scarring, lipodystrophy, penile girth enhancement, and vaginal augmentation. Adipose tissue–derived stem cells also are capable of differentiating into other types of tissue, including cartilage and bone. Thus, they have been successfully harnessed in the treatment of patients affected by systemic sclerosis and Parry-Romberg syndrome as well in the functional and aesthetic reconstruction of various military combat–related deformities.^9,10

Adipose tissue–derived stem cells are commonly harvested from lipoaspirate of the abdomen and are combined with supportive mechanical scaffolds such as hydrogels. Lipoaspirate itself can serve as a scaffold for ASCs. Accordingly, ASCs also are being utilized as a scaffold for autologous fat transfer procedures in an effort to increase the viability of transplanted donor tissue, a process known as cell-assisted lipotransfer (CAL). In CAL, a fraction of the aspirated fat is processed for isolation of ASCs, which are then recombined with the remainder of the aspirated fat prior to grafting.¹¹ However, there is conflicting evidence as to whether CAL leads to improved graft success relative to conventional autologous fat transfer.^12,13

The skin also serves as an easily accessible and abundant autologous source of stem cells. A subtype of dermal fibroblasts has been proven to have multipotent potential.^14,15 These dermal fibroblasts are harvested from one area of the skin using punch biopsy and are processed and reinjected into another desired area of the skin.¹⁶ Autologous human fibroblasts have proven to be effective for the treatment of wrinkles, rhytides, and acne scars.¹⁷ In June 2011, the US Food and Drug Administration approved azficel-T, an autologous cellular product created by harvesting fibroblasts from a patient’s own postauricular skin, culture-expanding them in vitro for 3 months, and reinjecting the cells into the desired area of dermis in a series of treatments. This product was the first personalized cell therapy approved by the US Food and Drug Administration for aesthetic uses, specifically for the improvement of nasolabial fold wrinkles.¹⁸

In adults, hair follicles contain an area known as the bulge, which is a site rich in epithelial and melanocytic stem cells. Bulge stem cells have the ability to reproduce the interfollicular epidermis, hair follicle structures, and sebaceous glands, and they have been used to construct entirely new hair follicles in an artificial in vivo system.¹⁹ Sugiyama-Nakagiri et al²⁰ demonstrated that an entire hair follicle epithelium and interfollicular epidermis can be regenerated using cultured bulge stem cells. The cultured bulge stem cells were mixed with dermal papilla cells from neonatal rat vibrissae and engrafted into a silicone chamber implanted on the backs of severe combined immune deficient (SCID) mice. The grafts exhibited tufts of hair as well as a complete interfollicular epidermis at 4 weeks after transplantation.²⁰ Thus, these bulge stem cells have the potential to treat male androgenic alopecia and female pattern hair loss. Bulge stem cells also have been shown to accelerate wound healing.²¹ Additionally, autologous melanocytic stem cells located at the hair follicle bulge are effective for treating vitiligo and are being investigated for the treatment of hair graying.²²

Induced Pluripotent Stem Cells

Given the ethical concerns that surround the procurement and use of embryonic stem cells, efforts have been made to retrieve pluripotent stem cells from adults. A major breakthrough occurred in 2006 when researchers altered the genes of specialized adult mouse cells to cause dedifferentiation and the return to an embryoniclike stem cell state.²³ Mouse somatic cells were reprogrammed through the activation of a combination of transcription factors. The resulting cells were termed induced pluripotent stem cells (iPSCs) and have since been recreated in human cell lines. The discovery of iPSCs precipitated a translational science revolution. Physician-scientists sought ways to apply the reprogrammed cells to the pathophysiology of obscure diseases, examination of drug targets, and regeneration of human tissue.²⁴ Tissue regeneration via induced naïve somatic cells has shown promise as a future method to treat neurologic, cardiovascular, and ophthalmologic diseases.²⁵

As the technology of cultivating and identifying optimal sources of iPSCs continues to advance, stem cell–based treatments have evolved as leading prospects in the field of biogerontology.^26-29 Although much of the research in antiaging medicine has utilized iPSCs to reprogram cell senescence, the altering of iPSCs at a cellular level also allows for the stimulation of collagen synthesis. This potential for collagen generation may have direct applicability in dermatologic practice, particularly for aesthetic treatments.

Much of the research into iPSC-derived collagen has focused on genodermatoses. Itoh et al³⁰ examined the creation of collagen through iPSCs to identify possible treatments for recessive dystrophic epidermolysis bullosa (DEB). Recessive DEB is characterized by mutations in the COL7A1 gene, which encodes type VII collagen, a basement membrane protein and component of the anchoring fibrils essential for skin integrity.³¹ Itoh et al³⁰ began with source cells obtained from a skin biopsy. The cells were dedifferentiated to iPSCs and then induced into dermal fibroblasts according to the methods established in prior studies of embryonic stem cells, namely with the use of ascorbic acid and transforming growth factor b. The newly formed fibroblasts were determined to be functional based on their ability to synthesize mature type VII collagen.³⁰ Once the viability of the iPSC-derived fibroblasts was confirmed in vitro, the cells were further tested through combination with human keratinocytes on SCID mice. The human keratinocytes grew together with the iPSC-derived fibroblasts, producing type VII collagen in the basement membrane zone and creating an epidermis with the normal markers.³⁰ Similarly, Robbins et al³² utilized SCID mice to successfully demonstrate that the transfection of keratinocytes from patients with junctional epidermolysis bullosa into SCID mice produced phenotypically normal skin.

Sebastiano et al³³ combined the concepts of iPSCs and genome editing in another study of recessive DEB. The investigators first cultured iPSCs from biopsies of affected patients. After deriving iPSCs and correcting their mutation via adenovirus-associated viral gene editing, the COL7A1 mutation-free cells were differentiated into keratinocytes. These iPSC-derived keratinocytes were subsequently grafted onto mice, which led to the production of wild-type collagen VII and a stratified epidermis. Despite this successful outcome, the grafts of iPSC-derived epidermis did not survive longer than 1 month.³³

One of the many obstacles facing the practical use of stem cells is their successful incorporation into human tissue. A possible solution was uncovered by Zhang et al³⁴ who examined iPSC-derived MSCs. Mesenchymal stem cells communicate via paracrine mechanisms, whereby exosomes containing RNA and proteins are released to potentiate a regenerative effect.³⁵ Zhang et al³⁴ found that injecting exosomes from human iPSC-derived MSCs into the wound sites of rats stimulated the production of type I collagen, type III collagen, and elastin. The wound sites demonstrated accelerated closure, narrower scar widths, and increased collagen maturity.

Understanding the role that local environment plays in stem cell differentiation, Xu et al³⁶ aimed to create an extracellular scaffold to induce fibroblast behavior from iPSCs. The authors engineered a framework similar to the normal extracellular membrane using proteoglycans, glycosaminoglycans, fibrinogen, and connective tissue growth factor. The iPSCs were then applied to the scaffolding, which led to successful fibroblast differentiation and type I collagen synthesis.³⁶ This use of local biosignaling cues holds important ramifications for controlling the fate of stem cells that have been introduced into a new environment.

Although the application of iPSCs in clinical dermatology has yet to be achieved, progress in the field is moving at a rapid pace. Several logistical elements require further mastery before therapeutics can be delivered. These areas include the optimal environment for iPSC differentiation, methods for maximization of graft survival, and different modes of transplanting iPSC-derived cells into patients. In cosmetic practice, success will depend on intradermal injections of collagen-producing iPSC-derived cells that possess long-term proliferative potential. Current research in mice models has demonstrated viability up to 16 weeks after intradermal injection of such cells.³⁷

Plant Stem Cells

In discussing the dermatologic applications of stem cell technology, clinicians should be aware of the plant stem cell products that have become a popular cosmeceutical trend. Companies advertise plant cells as a natural source of regenerative cells that can induce rejuvenation in human skin; however, there are no significant data to indicate that plant stem cells encourage or activate cellular growth in humans. Indeed, for stem cells to differentiate and produce viable components, the cells must first be incorporated as living components in the host tissue. Because plant stem cells do not survive in human tissue and plant cell cytokines fail to interact with the receptors on human cells, their current value in cosmeceuticals may be overstated.

Platelet-Rich Plasma

Platelet-rich plasma also is commonly associated with stem cell therapy, as PRP is known to potentiate stem cell proliferation, migration, and differentiation. However, PRP does not contain stem cells and is instead autologous plasma concentrated with platelets. In fact, platelets cannot even be classified as cells given that they lack a nucleus; platelets are considered cell fragments. The regenerative potential of PRP can be attributed to the growth factors released from platelets, which play an important role in tissue regeneration and repair. Platelet-rich plasma currently is being used in dermatology for skin rejuvenation (reduction of wrinkles and furrows) and treatment of acne scars.³⁸ There also is evidence supporting the effectiveness of PRP for alopecia and wound therapy, as growth factors play a vital role in hair growth and wound healing.³⁸ Apart from the use of PRP on its own, it can be used as a supplement to enhance the effects of antiaging procedures such as microneedling.³⁹

Future Directions

Multipotent stem cells and iPSCs discussed herein provide much promise in the field of regenerative dermatology. They are increasingly accessible and circumvent the use of ethically questionable embryonic stem cells. Although there is a general consensus on the great potential of stem cells for treating aesthetic skin conditions, high-quality randomized controlled trials remain scarce within the literature. Recognizing and optimizing these opportunities remains the next step in the future delivery of evidence-based care in regenerative dermatology.

Regenerative medicine encompasses innovative therapies that allow the body to repair or regenerate aging cells, tissues, and organs. The skin is a particularly attractive organ for the application of novel regenerative therapies due to its easy accessibility. Among these therapies, stem cells and platelet-rich plasma (PRP) have garnered interest based on their therapeutic potential in scar reduction, antiaging effects, and treatment of alopecia.

Stem cells possess the cardinal features of self-renewal and plasticity. Self-renewal refers to symmetric cell division generating daughter cells identical to the parent cell.¹ Plasticity is the ability to generate cell types other than the germ line or tissue lineage from which stem cells derive.² Stem cells can be categorized according to their differentiation potential. Totipotent stem cells may develop into any primary germ cell layer (ectoderm, mesoderm, endoderm) of the embryo, as well as extraembryonic tissue such as the trophoblast, which gives rise to the placenta. Pluripotent stem cells such as embryonic stem cells have the capacity to differentiate into any derivative of the 3 germ cell layers but have lost their ability to differentiate into the trophoblast.³ Adults lack totipotent or pluripotent cells; they have multipotent or unipotent cells. Multipotent stem cells are able to differentiate into multiple cell types from similar lineages; mesenchymal stem cells (MSCs), for example, can differentiate into adipogenic, osteogenic, chondrogenic, and myogenic cells.⁴ Unipotent stem cells have the lowest differentiation potential and can only self-regenerate. Herein, we review stem cell sources and their therapeutic potential in aesthetic dermatology.

Multipotent Stem Cells

Multipotent stem cells derived from the bone marrow, umbilical cord, adipose tissue, dermis, or hair follicle bulge have various clinical applications in dermatology. Stem cells from these sources are primarily utilized in an autologous manner in which they are processed outside the body and reintroduced into the donor. Autologous multipotent hematopoietic bone marrow cells were first successfully used for the treatment of chronic wounds and show promise for the treatment of atrophic scars.^5,6 However, due to the invasive nature of extracting bone marrow stem cells and their declining number with age, other sources of multipotent stem cells have fallen into favor.

Umbilical cord blood is a source of multipotent hematopoietic stem cells for which surgical intervention is not necessary because they are retrieved after umbilical cord clamping.⁷ Advantages of sourcing stem cells from umbilical cord blood includes high regenerative power compared to a newborn’s skin and low immunogenicity given that the newborn is immunologically immature.⁸

Another popular source for autologous stem cells is adipose tissue due to its ease of accessibility and relative abundance. Given that adipose tissue–derived stem cells (ASCs) are capable of differentiating into adipocytes that help maintain volume over time, they are being used for midface contouring, lip augmentation, facial rejuvenation, facial scarring, lipodystrophy, penile girth enhancement, and vaginal augmentation. Adipose tissue–derived stem cells also are capable of differentiating into other types of tissue, including cartilage and bone. Thus, they have been successfully harnessed in the treatment of patients affected by systemic sclerosis and Parry-Romberg syndrome as well in the functional and aesthetic reconstruction of various military combat–related deformities.^9,10

Adipose tissue–derived stem cells are commonly harvested from lipoaspirate of the abdomen and are combined with supportive mechanical scaffolds such as hydrogels. Lipoaspirate itself can serve as a scaffold for ASCs. Accordingly, ASCs also are being utilized as a scaffold for autologous fat transfer procedures in an effort to increase the viability of transplanted donor tissue, a process known as cell-assisted lipotransfer (CAL). In CAL, a fraction of the aspirated fat is processed for isolation of ASCs, which are then recombined with the remainder of the aspirated fat prior to grafting.¹¹ However, there is conflicting evidence as to whether CAL leads to improved graft success relative to conventional autologous fat transfer.^12,13

The skin also serves as an easily accessible and abundant autologous source of stem cells. A subtype of dermal fibroblasts has been proven to have multipotent potential.^14,15 These dermal fibroblasts are harvested from one area of the skin using punch biopsy and are processed and reinjected into another desired area of the skin.¹⁶ Autologous human fibroblasts have proven to be effective for the treatment of wrinkles, rhytides, and acne scars.¹⁷ In June 2011, the US Food and Drug Administration approved azficel-T, an autologous cellular product created by harvesting fibroblasts from a patient’s own postauricular skin, culture-expanding them in vitro for 3 months, and reinjecting the cells into the desired area of dermis in a series of treatments. This product was the first personalized cell therapy approved by the US Food and Drug Administration for aesthetic uses, specifically for the improvement of nasolabial fold wrinkles.¹⁸

In adults, hair follicles contain an area known as the bulge, which is a site rich in epithelial and melanocytic stem cells. Bulge stem cells have the ability to reproduce the interfollicular epidermis, hair follicle structures, and sebaceous glands, and they have been used to construct entirely new hair follicles in an artificial in vivo system.¹⁹ Sugiyama-Nakagiri et al²⁰ demonstrated that an entire hair follicle epithelium and interfollicular epidermis can be regenerated using cultured bulge stem cells. The cultured bulge stem cells were mixed with dermal papilla cells from neonatal rat vibrissae and engrafted into a silicone chamber implanted on the backs of severe combined immune deficient (SCID) mice. The grafts exhibited tufts of hair as well as a complete interfollicular epidermis at 4 weeks after transplantation.²⁰ Thus, these bulge stem cells have the potential to treat male androgenic alopecia and female pattern hair loss. Bulge stem cells also have been shown to accelerate wound healing.²¹ Additionally, autologous melanocytic stem cells located at the hair follicle bulge are effective for treating vitiligo and are being investigated for the treatment of hair graying.²²

Induced Pluripotent Stem Cells

Given the ethical concerns that surround the procurement and use of embryonic stem cells, efforts have been made to retrieve pluripotent stem cells from adults. A major breakthrough occurred in 2006 when researchers altered the genes of specialized adult mouse cells to cause dedifferentiation and the return to an embryoniclike stem cell state.²³ Mouse somatic cells were reprogrammed through the activation of a combination of transcription factors. The resulting cells were termed induced pluripotent stem cells (iPSCs) and have since been recreated in human cell lines. The discovery of iPSCs precipitated a translational science revolution. Physician-scientists sought ways to apply the reprogrammed cells to the pathophysiology of obscure diseases, examination of drug targets, and regeneration of human tissue.²⁴ Tissue regeneration via induced naïve somatic cells has shown promise as a future method to treat neurologic, cardiovascular, and ophthalmologic diseases.²⁵

As the technology of cultivating and identifying optimal sources of iPSCs continues to advance, stem cell–based treatments have evolved as leading prospects in the field of biogerontology.^26-29 Although much of the research in antiaging medicine has utilized iPSCs to reprogram cell senescence, the altering of iPSCs at a cellular level also allows for the stimulation of collagen synthesis. This potential for collagen generation may have direct applicability in dermatologic practice, particularly for aesthetic treatments.

Much of the research into iPSC-derived collagen has focused on genodermatoses. Itoh et al³⁰ examined the creation of collagen through iPSCs to identify possible treatments for recessive dystrophic epidermolysis bullosa (DEB). Recessive DEB is characterized by mutations in the COL7A1 gene, which encodes type VII collagen, a basement membrane protein and component of the anchoring fibrils essential for skin integrity.³¹ Itoh et al³⁰ began with source cells obtained from a skin biopsy. The cells were dedifferentiated to iPSCs and then induced into dermal fibroblasts according to the methods established in prior studies of embryonic stem cells, namely with the use of ascorbic acid and transforming growth factor b. The newly formed fibroblasts were determined to be functional based on their ability to synthesize mature type VII collagen.³⁰ Once the viability of the iPSC-derived fibroblasts was confirmed in vitro, the cells were further tested through combination with human keratinocytes on SCID mice. The human keratinocytes grew together with the iPSC-derived fibroblasts, producing type VII collagen in the basement membrane zone and creating an epidermis with the normal markers.³⁰ Similarly, Robbins et al³² utilized SCID mice to successfully demonstrate that the transfection of keratinocytes from patients with junctional epidermolysis bullosa into SCID mice produced phenotypically normal skin.

Sebastiano et al³³ combined the concepts of iPSCs and genome editing in another study of recessive DEB. The investigators first cultured iPSCs from biopsies of affected patients. After deriving iPSCs and correcting their mutation via adenovirus-associated viral gene editing, the COL7A1 mutation-free cells were differentiated into keratinocytes. These iPSC-derived keratinocytes were subsequently grafted onto mice, which led to the production of wild-type collagen VII and a stratified epidermis. Despite this successful outcome, the grafts of iPSC-derived epidermis did not survive longer than 1 month.³³

One of the many obstacles facing the practical use of stem cells is their successful incorporation into human tissue. A possible solution was uncovered by Zhang et al³⁴ who examined iPSC-derived MSCs. Mesenchymal stem cells communicate via paracrine mechanisms, whereby exosomes containing RNA and proteins are released to potentiate a regenerative effect.³⁵ Zhang et al³⁴ found that injecting exosomes from human iPSC-derived MSCs into the wound sites of rats stimulated the production of type I collagen, type III collagen, and elastin. The wound sites demonstrated accelerated closure, narrower scar widths, and increased collagen maturity.

Understanding the role that local environment plays in stem cell differentiation, Xu et al³⁶ aimed to create an extracellular scaffold to induce fibroblast behavior from iPSCs. The authors engineered a framework similar to the normal extracellular membrane using proteoglycans, glycosaminoglycans, fibrinogen, and connective tissue growth factor. The iPSCs were then applied to the scaffolding, which led to successful fibroblast differentiation and type I collagen synthesis.³⁶ This use of local biosignaling cues holds important ramifications for controlling the fate of stem cells that have been introduced into a new environment.

Although the application of iPSCs in clinical dermatology has yet to be achieved, progress in the field is moving at a rapid pace. Several logistical elements require further mastery before therapeutics can be delivered. These areas include the optimal environment for iPSC differentiation, methods for maximization of graft survival, and different modes of transplanting iPSC-derived cells into patients. In cosmetic practice, success will depend on intradermal injections of collagen-producing iPSC-derived cells that possess long-term proliferative potential. Current research in mice models has demonstrated viability up to 16 weeks after intradermal injection of such cells.³⁷

Plant Stem Cells

In discussing the dermatologic applications of stem cell technology, clinicians should be aware of the plant stem cell products that have become a popular cosmeceutical trend. Companies advertise plant cells as a natural source of regenerative cells that can induce rejuvenation in human skin; however, there are no significant data to indicate that plant stem cells encourage or activate cellular growth in humans. Indeed, for stem cells to differentiate and produce viable components, the cells must first be incorporated as living components in the host tissue. Because plant stem cells do not survive in human tissue and plant cell cytokines fail to interact with the receptors on human cells, their current value in cosmeceuticals may be overstated.

Platelet-Rich Plasma

Platelet-rich plasma also is commonly associated with stem cell therapy, as PRP is known to potentiate stem cell proliferation, migration, and differentiation. However, PRP does not contain stem cells and is instead autologous plasma concentrated with platelets. In fact, platelets cannot even be classified as cells given that they lack a nucleus; platelets are considered cell fragments. The regenerative potential of PRP can be attributed to the growth factors released from platelets, which play an important role in tissue regeneration and repair. Platelet-rich plasma currently is being used in dermatology for skin rejuvenation (reduction of wrinkles and furrows) and treatment of acne scars.³⁸ There also is evidence supporting the effectiveness of PRP for alopecia and wound therapy, as growth factors play a vital role in hair growth and wound healing.³⁸ Apart from the use of PRP on its own, it can be used as a supplement to enhance the effects of antiaging procedures such as microneedling.³⁹

Future Directions

Multipotent stem cells and iPSCs discussed herein provide much promise in the field of regenerative dermatology. They are increasingly accessible and circumvent the use of ethically questionable embryonic stem cells. Although there is a general consensus on the great potential of stem cells for treating aesthetic skin conditions, high-quality randomized controlled trials remain scarce within the literature. Recognizing and optimizing these opportunities remains the next step in the future delivery of evidence-based care in regenerative dermatology.

The Food and Drug Administration has approved ozenoxacin cream 1% (Xepi), a topical antibiotic for treating impetigo attributable to Staphylococcus aureus or Streptococcus pyogenes in patients aged 2 months or older.

This is the first topical treatment for impetigo to be approved in more than 10 years, according to the press release from the manufacturer, Medimetriks Pharmaceuticals.

[email protected]

The Food and Drug Administration has approved ozenoxacin cream 1% (Xepi), a topical antibiotic for treating impetigo attributable to Staphylococcus aureus or Streptococcus pyogenes in patients aged 2 months or older.

This is the first topical treatment for impetigo to be approved in more than 10 years, according to the press release from the manufacturer, Medimetriks Pharmaceuticals.

[email protected]

The Food and Drug Administration has approved ozenoxacin cream 1% (Xepi), a topical antibiotic for treating impetigo attributable to Staphylococcus aureus or Streptococcus pyogenes in patients aged 2 months or older.

This is the first topical treatment for impetigo to be approved in more than 10 years, according to the press release from the manufacturer, Medimetriks Pharmaceuticals.

[email protected]

Chronic diabetic foot ulcers (DFUs) remain a serious therapeutic challenge worldwide.^1-2 Patients with DFUs are at higher risk for infections, which may lead to limb loss.^1-5 In fact, 1 in 6 patients with DFUs will undergo an amputation.⁶ The long-term consequences of DFUs are numerous and can severely affect patients’ quality of life, including loss of productivity.⁷ The current standard of care for DFUs consists of debridement of the necrotic tissue, application of a moist dressing, and use of an off-loading device that protects the wound from pressure or trauma related to ambulation and other acts of daily living.^4-6,8 Unfortunately, studies have shown that the best standard of care (SOC) only heals 30% of DFUs after 20 weeks of therapy.⁹ With the estimated cost per episode of care approaching $40,000, DFUs remain a costly and important problem.¹⁰

The altered extracellular matrix (ECM) in DFUs has been a target for the development of new therapeutic devices that provide a new matrix that is either devoid of cells or can be enriched with fibroblasts.^8,11 These bioengineered skin substitutes stimulate the growth of new vessels and generate cytokines essential for tissue repair. In 2013, Lev-Tov et al¹² published this study protocol (Dermagraft Oasis Longitudinal Comparative Efficacy [DOLCE] trial) to compare the effectiveness of 2 advanced wound care devices, specifically to evaluate the clinical efficacy of a cellular matrix versus an acellular matrix, which we have amended. The cellular matrix used in the study is a dermal substitute composed of viable newborn foreskin fibroblasts seeded onto a bioabsorbable polyglactin mesh on which fibroblasts generate an ECM.^13,14 It is supplied frozen and requires specific thawing steps prior to application. The recommended regimen for treatment of DFUs for this cellular matrix is 8 weekly applications.^13,14 In 2016, the cost of the product was reported as $1411 per 5.0×7.5-cm sheet.¹⁵ The acellular matrix product used in the study is a bioabsorbable ECM that is derived from porcine small intestinal submucosa.^16,17 It is stored at room temperature and has a long shelf life, with a current price of $112.6 for a 3.0×3.5-cm single-layer fenestrated sheet ($1126.60 per box of 10 sheets). The industry-supported randomized controlled trials for each of these devices have reported a 20% added benefit in the rate of wound closure at week 12 compared to SOC.^14,17However, our hypothesis is that these therapeutic devices will yield equivalent clinical outcomes, each being equally more effective than SOC, supporting the wider adoption of the less expensive, cell-free matrix device that has a longer shelf life and is easier to apply.

This article provides the interim report of the trial (registered at www.clinicaltrials.gov with the identifier NCT01450943) described in the published protocol and initiated in 2011,¹² focusing on elements that required modification during the trial’s duration.

Methods

Study Protocol
The clinical trial was approved by the Veterans’ Affairs Institutional Research and Development Committee and their institutional review board. This study was funded by the Veteran’s Administration Merit Award (#10554640), which was awarded to 2 of the investigators (S.E.D. and R.R.I.). Eligible veterans were recruited from all 7 sites of the VA Northern California Healthcare System. This trial is a randomized, single-blinded, 3-armed, controlled clinical equivalence trial comparing the effectiveness of an SOC treatment, cellular ECM, and acellular ECM.

Study Products
The SOC dressing applied in the clinical trial included a sterile antimicrobial gel, a nonadherent dressing, and gauze.¹² The SOC dressing also was used as a secondary dressing for the active treatment arms. Bacitracin antibiotic ointment was used as an alternative for patients with allergy to iodine.¹²

Randomization
The inclusion and exclusion criteria were previously outlined.¹² After a 2-week screening phase to exclude rapid healers, patients were randomized into a treatment arm and entered the active phase for 12 weeks. Patients then were seen once monthly for 16 weeks in a follow-up phase.¹²

Primary and Secondary Outcomes
The primary outcome was complete wound closure by week 12.¹² Complete healing was defined as full reepithelialization with no drainage or dressing requirement. The secondary outcomes included healing at 28 weeks, rate of healing, ulcer recurrence at week 20, association of wound healing with ulcer characteristics or patients’ characteristic, incidence of adverse events, and cost-effectiveness of each treatment compared to the SOC arm.¹²

Statistical Analysis
To detect a 25% difference in the incidence of ulcer closure between the 2 study groups and the SOC group, the estimation of the sample size was based on 80% power with a significance level of 0.05. Specifically, it was expected that 50% of the cellular and acellular matrix groups and 25% of the SOC group would reach complete wound closure. The protocol indicated that 57 participants would be enrolled in each arm (total of 171 participants). Lev-Tov et al¹² discussed the statistical analysis in more detail.

Results

Study Protocol Amendments
Given the number of diabetic patients in the US veteran population, we anticipated that there would be enough participants meeting the inclusion and exclusion criteria; however, because of the difficulty with recruitment, the initial study criteria were modified. The study was initially designed to incorporate DFUs with a minimum size of 1.0 cm².¹²The study investigators noted that within the veteran population, many diabetic patients with DFUs had ulcers that were too small to meet the inclusion criteria; thus, these patients could not be captured in the trial. However, those small ulcers would stall for months, which prompted the decision to change this major exclusion criterion to allow patients with a wound size greater than 0.5 cm² (versus 1.0 cm²) to be recruited. Enrollment of participants also was extended to include nonveterans.

Another limiting criterion was the percentage of total hemoglobin level for hemoglobin A_1C (HbA_1C). The study was originally established to include participants with an HbA_1C level of 10% of total hemoglobin or below.¹² Unfortunately, the majority of the potential participants had values substantially higher, and thus could not be enrolled in the trial, requiring another amendment to the study protocol in 2014, which was approved to include patients with an HbA_1C level less than 12% of total hemoglobin. This change contributed considerably to the noted increase in enrollment rates in 2015, which almost doubled relative to enrollment under the original exclusion criteria (Figure).

The study has screened more than 600 patients. Among them, 137 were assessed for eligibility; 71 were excluded for various reasons, including screen failure (eg, decrease in wound size by >40% during the 2-week screening phase), loss to follow-up, and adverse events. Sixty-six participants reached the primary outcome at week 12, while 55 participants completed the study (19 in the SOC group; 18 in the cellular matrix group; 18 in the acellular matrix group).

We have stopped enrolling patients from all sites and the community, as we have reached our target enrollment.

Comment

One of the challenges of clinical trials is the recruitment of an adequate number of participants within an appropriate time frame, which is explained by Lasagna’s Law,¹⁸ a well-described phenomenon whereby the investigator overestimates the number of potential participants available to meet the inclusion criteria. This so-called funnel-effect was partly encountered in our selection process. A review of the veteran population with DFUs seemed to be more than adequate to fulfill the sample size; however, some important participant-related factors also played a substantial role. The criterion for minimum ulcer size of 1.0 cm² was comparable to other trials⁸ but was a major limiting factor in our study. Many participants already were established with either the podiatry or multispecialty wound clinics, and they had small DFUs, which were stalling for months. Thus, by decreasing the lesion size needed for inclusion, our trial benefited from this subset population.

In addition, the Veterans’ Affairs network centralizes health information, making it readily available to all providers participating in their care. As a result, patients with diabetes mellitus typically are seen by a primary care physician along with an endocrinologist, a diabetic nurse, and/or a dietician. Despite the collaboration with an interdisciplinary team, the glycemic control of the participants remains an issue along with other psychosocial factors that are deterrents in patient compliance. As a result, patients with poorly controlled diabetes and an HbA_1C level above 10% (and less than 12%) of total hemoglobin who were initially excluded from the study were reincluded after modifying the inclusion criteria. Some patients were interested in joining the study, but physical limitations (eg, impaired mobility) prompted their decision not to join the trial, even though they met all the inclusion criteria.

As far as research-related factors that could affect participation, it is notable that most of the patients were retired; thus, the interventions did not cause additional burden of taking time off from work or loss of productivity. Although randomization could be a deterrent in many clinical trials, the majority of patients were willing to participate without demanding to be assigned to a particular treatment group. Some research-related factors that were an impediment to patient enrollment included the time to travel and the associated expenses, but our trial was designed to offer a small stipend for travel reimbursement (up to $400) to mitigate such factors.

There are many factors that are intertwined and can lead to enrollment and/or attrition rates. It was critical for our team to make some adjustment without compromising the controlled nature of a randomized trial.

Acknowledgment
The authors wish to acknowledge Huong Le, DPM, MPH, who was the coauthor of the study protocol.

Chronic diabetic foot ulcers (DFUs) remain a serious therapeutic challenge worldwide.^1-2 Patients with DFUs are at higher risk for infections, which may lead to limb loss.^1-5 In fact, 1 in 6 patients with DFUs will undergo an amputation.⁶ The long-term consequences of DFUs are numerous and can severely affect patients’ quality of life, including loss of productivity.⁷ The current standard of care for DFUs consists of debridement of the necrotic tissue, application of a moist dressing, and use of an off-loading device that protects the wound from pressure or trauma related to ambulation and other acts of daily living.^4-6,8 Unfortunately, studies have shown that the best standard of care (SOC) only heals 30% of DFUs after 20 weeks of therapy.⁹ With the estimated cost per episode of care approaching $40,000, DFUs remain a costly and important problem.¹⁰

The altered extracellular matrix (ECM) in DFUs has been a target for the development of new therapeutic devices that provide a new matrix that is either devoid of cells or can be enriched with fibroblasts.^8,11 These bioengineered skin substitutes stimulate the growth of new vessels and generate cytokines essential for tissue repair. In 2013, Lev-Tov et al¹² published this study protocol (Dermagraft Oasis Longitudinal Comparative Efficacy [DOLCE] trial) to compare the effectiveness of 2 advanced wound care devices, specifically to evaluate the clinical efficacy of a cellular matrix versus an acellular matrix, which we have amended. The cellular matrix used in the study is a dermal substitute composed of viable newborn foreskin fibroblasts seeded onto a bioabsorbable polyglactin mesh on which fibroblasts generate an ECM.^13,14 It is supplied frozen and requires specific thawing steps prior to application. The recommended regimen for treatment of DFUs for this cellular matrix is 8 weekly applications.^13,14 In 2016, the cost of the product was reported as $1411 per 5.0×7.5-cm sheet.¹⁵ The acellular matrix product used in the study is a bioabsorbable ECM that is derived from porcine small intestinal submucosa.^16,17 It is stored at room temperature and has a long shelf life, with a current price of $112.6 for a 3.0×3.5-cm single-layer fenestrated sheet ($1126.60 per box of 10 sheets). The industry-supported randomized controlled trials for each of these devices have reported a 20% added benefit in the rate of wound closure at week 12 compared to SOC.^14,17However, our hypothesis is that these therapeutic devices will yield equivalent clinical outcomes, each being equally more effective than SOC, supporting the wider adoption of the less expensive, cell-free matrix device that has a longer shelf life and is easier to apply.

This article provides the interim report of the trial (registered at www.clinicaltrials.gov with the identifier NCT01450943) described in the published protocol and initiated in 2011,¹² focusing on elements that required modification during the trial’s duration.

Methods

Study Protocol
The clinical trial was approved by the Veterans’ Affairs Institutional Research and Development Committee and their institutional review board. This study was funded by the Veteran’s Administration Merit Award (#10554640), which was awarded to 2 of the investigators (S.E.D. and R.R.I.). Eligible veterans were recruited from all 7 sites of the VA Northern California Healthcare System. This trial is a randomized, single-blinded, 3-armed, controlled clinical equivalence trial comparing the effectiveness of an SOC treatment, cellular ECM, and acellular ECM.

Study Products
The SOC dressing applied in the clinical trial included a sterile antimicrobial gel, a nonadherent dressing, and gauze.¹² The SOC dressing also was used as a secondary dressing for the active treatment arms. Bacitracin antibiotic ointment was used as an alternative for patients with allergy to iodine.¹²

Randomization
The inclusion and exclusion criteria were previously outlined.¹² After a 2-week screening phase to exclude rapid healers, patients were randomized into a treatment arm and entered the active phase for 12 weeks. Patients then were seen once monthly for 16 weeks in a follow-up phase.¹²

Primary and Secondary Outcomes
The primary outcome was complete wound closure by week 12.¹² Complete healing was defined as full reepithelialization with no drainage or dressing requirement. The secondary outcomes included healing at 28 weeks, rate of healing, ulcer recurrence at week 20, association of wound healing with ulcer characteristics or patients’ characteristic, incidence of adverse events, and cost-effectiveness of each treatment compared to the SOC arm.¹²

Statistical Analysis
To detect a 25% difference in the incidence of ulcer closure between the 2 study groups and the SOC group, the estimation of the sample size was based on 80% power with a significance level of 0.05. Specifically, it was expected that 50% of the cellular and acellular matrix groups and 25% of the SOC group would reach complete wound closure. The protocol indicated that 57 participants would be enrolled in each arm (total of 171 participants). Lev-Tov et al¹² discussed the statistical analysis in more detail.

Results

Study Protocol Amendments
Given the number of diabetic patients in the US veteran population, we anticipated that there would be enough participants meeting the inclusion and exclusion criteria; however, because of the difficulty with recruitment, the initial study criteria were modified. The study was initially designed to incorporate DFUs with a minimum size of 1.0 cm².¹²The study investigators noted that within the veteran population, many diabetic patients with DFUs had ulcers that were too small to meet the inclusion criteria; thus, these patients could not be captured in the trial. However, those small ulcers would stall for months, which prompted the decision to change this major exclusion criterion to allow patients with a wound size greater than 0.5 cm² (versus 1.0 cm²) to be recruited. Enrollment of participants also was extended to include nonveterans.

Another limiting criterion was the percentage of total hemoglobin level for hemoglobin A_1C (HbA_1C). The study was originally established to include participants with an HbA_1C level of 10% of total hemoglobin or below.¹² Unfortunately, the majority of the potential participants had values substantially higher, and thus could not be enrolled in the trial, requiring another amendment to the study protocol in 2014, which was approved to include patients with an HbA_1C level less than 12% of total hemoglobin. This change contributed considerably to the noted increase in enrollment rates in 2015, which almost doubled relative to enrollment under the original exclusion criteria (Figure).

The study has screened more than 600 patients. Among them, 137 were assessed for eligibility; 71 were excluded for various reasons, including screen failure (eg, decrease in wound size by >40% during the 2-week screening phase), loss to follow-up, and adverse events. Sixty-six participants reached the primary outcome at week 12, while 55 participants completed the study (19 in the SOC group; 18 in the cellular matrix group; 18 in the acellular matrix group).

We have stopped enrolling patients from all sites and the community, as we have reached our target enrollment.

Comment

One of the challenges of clinical trials is the recruitment of an adequate number of participants within an appropriate time frame, which is explained by Lasagna’s Law,¹⁸ a well-described phenomenon whereby the investigator overestimates the number of potential participants available to meet the inclusion criteria. This so-called funnel-effect was partly encountered in our selection process. A review of the veteran population with DFUs seemed to be more than adequate to fulfill the sample size; however, some important participant-related factors also played a substantial role. The criterion for minimum ulcer size of 1.0 cm² was comparable to other trials⁸ but was a major limiting factor in our study. Many participants already were established with either the podiatry or multispecialty wound clinics, and they had small DFUs, which were stalling for months. Thus, by decreasing the lesion size needed for inclusion, our trial benefited from this subset population.

In addition, the Veterans’ Affairs network centralizes health information, making it readily available to all providers participating in their care. As a result, patients with diabetes mellitus typically are seen by a primary care physician along with an endocrinologist, a diabetic nurse, and/or a dietician. Despite the collaboration with an interdisciplinary team, the glycemic control of the participants remains an issue along with other psychosocial factors that are deterrents in patient compliance. As a result, patients with poorly controlled diabetes and an HbA_1C level above 10% (and less than 12%) of total hemoglobin who were initially excluded from the study were reincluded after modifying the inclusion criteria. Some patients were interested in joining the study, but physical limitations (eg, impaired mobility) prompted their decision not to join the trial, even though they met all the inclusion criteria.

As far as research-related factors that could affect participation, it is notable that most of the patients were retired; thus, the interventions did not cause additional burden of taking time off from work or loss of productivity. Although randomization could be a deterrent in many clinical trials, the majority of patients were willing to participate without demanding to be assigned to a particular treatment group. Some research-related factors that were an impediment to patient enrollment included the time to travel and the associated expenses, but our trial was designed to offer a small stipend for travel reimbursement (up to $400) to mitigate such factors.

There are many factors that are intertwined and can lead to enrollment and/or attrition rates. It was critical for our team to make some adjustment without compromising the controlled nature of a randomized trial.

Acknowledgment
The authors wish to acknowledge Huong Le, DPM, MPH, who was the coauthor of the study protocol.

Chronic diabetic foot ulcers (DFUs) remain a serious therapeutic challenge worldwide.^1-2 Patients with DFUs are at higher risk for infections, which may lead to limb loss.^1-5 In fact, 1 in 6 patients with DFUs will undergo an amputation.⁶ The long-term consequences of DFUs are numerous and can severely affect patients’ quality of life, including loss of productivity.⁷ The current standard of care for DFUs consists of debridement of the necrotic tissue, application of a moist dressing, and use of an off-loading device that protects the wound from pressure or trauma related to ambulation and other acts of daily living.^4-6,8 Unfortunately, studies have shown that the best standard of care (SOC) only heals 30% of DFUs after 20 weeks of therapy.⁹ With the estimated cost per episode of care approaching $40,000, DFUs remain a costly and important problem.¹⁰

The altered extracellular matrix (ECM) in DFUs has been a target for the development of new therapeutic devices that provide a new matrix that is either devoid of cells or can be enriched with fibroblasts.^8,11 These bioengineered skin substitutes stimulate the growth of new vessels and generate cytokines essential for tissue repair. In 2013, Lev-Tov et al¹² published this study protocol (Dermagraft Oasis Longitudinal Comparative Efficacy [DOLCE] trial) to compare the effectiveness of 2 advanced wound care devices, specifically to evaluate the clinical efficacy of a cellular matrix versus an acellular matrix, which we have amended. The cellular matrix used in the study is a dermal substitute composed of viable newborn foreskin fibroblasts seeded onto a bioabsorbable polyglactin mesh on which fibroblasts generate an ECM.^13,14 It is supplied frozen and requires specific thawing steps prior to application. The recommended regimen for treatment of DFUs for this cellular matrix is 8 weekly applications.^13,14 In 2016, the cost of the product was reported as $1411 per 5.0×7.5-cm sheet.¹⁵ The acellular matrix product used in the study is a bioabsorbable ECM that is derived from porcine small intestinal submucosa.^16,17 It is stored at room temperature and has a long shelf life, with a current price of $112.6 for a 3.0×3.5-cm single-layer fenestrated sheet ($1126.60 per box of 10 sheets). The industry-supported randomized controlled trials for each of these devices have reported a 20% added benefit in the rate of wound closure at week 12 compared to SOC.^14,17However, our hypothesis is that these therapeutic devices will yield equivalent clinical outcomes, each being equally more effective than SOC, supporting the wider adoption of the less expensive, cell-free matrix device that has a longer shelf life and is easier to apply.

This article provides the interim report of the trial (registered at www.clinicaltrials.gov with the identifier NCT01450943) described in the published protocol and initiated in 2011,¹² focusing on elements that required modification during the trial’s duration.

Methods

Study Protocol
The clinical trial was approved by the Veterans’ Affairs Institutional Research and Development Committee and their institutional review board. This study was funded by the Veteran’s Administration Merit Award (#10554640), which was awarded to 2 of the investigators (S.E.D. and R.R.I.). Eligible veterans were recruited from all 7 sites of the VA Northern California Healthcare System. This trial is a randomized, single-blinded, 3-armed, controlled clinical equivalence trial comparing the effectiveness of an SOC treatment, cellular ECM, and acellular ECM.

Study Products
The SOC dressing applied in the clinical trial included a sterile antimicrobial gel, a nonadherent dressing, and gauze.¹² The SOC dressing also was used as a secondary dressing for the active treatment arms. Bacitracin antibiotic ointment was used as an alternative for patients with allergy to iodine.¹²

Randomization
The inclusion and exclusion criteria were previously outlined.¹² After a 2-week screening phase to exclude rapid healers, patients were randomized into a treatment arm and entered the active phase for 12 weeks. Patients then were seen once monthly for 16 weeks in a follow-up phase.¹²

Primary and Secondary Outcomes
The primary outcome was complete wound closure by week 12.¹² Complete healing was defined as full reepithelialization with no drainage or dressing requirement. The secondary outcomes included healing at 28 weeks, rate of healing, ulcer recurrence at week 20, association of wound healing with ulcer characteristics or patients’ characteristic, incidence of adverse events, and cost-effectiveness of each treatment compared to the SOC arm.¹²

Statistical Analysis
To detect a 25% difference in the incidence of ulcer closure between the 2 study groups and the SOC group, the estimation of the sample size was based on 80% power with a significance level of 0.05. Specifically, it was expected that 50% of the cellular and acellular matrix groups and 25% of the SOC group would reach complete wound closure. The protocol indicated that 57 participants would be enrolled in each arm (total of 171 participants). Lev-Tov et al¹² discussed the statistical analysis in more detail.

Results

Study Protocol Amendments
Given the number of diabetic patients in the US veteran population, we anticipated that there would be enough participants meeting the inclusion and exclusion criteria; however, because of the difficulty with recruitment, the initial study criteria were modified. The study was initially designed to incorporate DFUs with a minimum size of 1.0 cm².¹²The study investigators noted that within the veteran population, many diabetic patients with DFUs had ulcers that were too small to meet the inclusion criteria; thus, these patients could not be captured in the trial. However, those small ulcers would stall for months, which prompted the decision to change this major exclusion criterion to allow patients with a wound size greater than 0.5 cm² (versus 1.0 cm²) to be recruited. Enrollment of participants also was extended to include nonveterans.

Another limiting criterion was the percentage of total hemoglobin level for hemoglobin A_1C (HbA_1C). The study was originally established to include participants with an HbA_1C level of 10% of total hemoglobin or below.¹² Unfortunately, the majority of the potential participants had values substantially higher, and thus could not be enrolled in the trial, requiring another amendment to the study protocol in 2014, which was approved to include patients with an HbA_1C level less than 12% of total hemoglobin. This change contributed considerably to the noted increase in enrollment rates in 2015, which almost doubled relative to enrollment under the original exclusion criteria (Figure).

The study has screened more than 600 patients. Among them, 137 were assessed for eligibility; 71 were excluded for various reasons, including screen failure (eg, decrease in wound size by >40% during the 2-week screening phase), loss to follow-up, and adverse events. Sixty-six participants reached the primary outcome at week 12, while 55 participants completed the study (19 in the SOC group; 18 in the cellular matrix group; 18 in the acellular matrix group).

We have stopped enrolling patients from all sites and the community, as we have reached our target enrollment.

Comment

One of the challenges of clinical trials is the recruitment of an adequate number of participants within an appropriate time frame, which is explained by Lasagna’s Law,¹⁸ a well-described phenomenon whereby the investigator overestimates the number of potential participants available to meet the inclusion criteria. This so-called funnel-effect was partly encountered in our selection process. A review of the veteran population with DFUs seemed to be more than adequate to fulfill the sample size; however, some important participant-related factors also played a substantial role. The criterion for minimum ulcer size of 1.0 cm² was comparable to other trials⁸ but was a major limiting factor in our study. Many participants already were established with either the podiatry or multispecialty wound clinics, and they had small DFUs, which were stalling for months. Thus, by decreasing the lesion size needed for inclusion, our trial benefited from this subset population.

In addition, the Veterans’ Affairs network centralizes health information, making it readily available to all providers participating in their care. As a result, patients with diabetes mellitus typically are seen by a primary care physician along with an endocrinologist, a diabetic nurse, and/or a dietician. Despite the collaboration with an interdisciplinary team, the glycemic control of the participants remains an issue along with other psychosocial factors that are deterrents in patient compliance. As a result, patients with poorly controlled diabetes and an HbA_1C level above 10% (and less than 12%) of total hemoglobin who were initially excluded from the study were reincluded after modifying the inclusion criteria. Some patients were interested in joining the study, but physical limitations (eg, impaired mobility) prompted their decision not to join the trial, even though they met all the inclusion criteria.

As far as research-related factors that could affect participation, it is notable that most of the patients were retired; thus, the interventions did not cause additional burden of taking time off from work or loss of productivity. Although randomization could be a deterrent in many clinical trials, the majority of patients were willing to participate without demanding to be assigned to a particular treatment group. Some research-related factors that were an impediment to patient enrollment included the time to travel and the associated expenses, but our trial was designed to offer a small stipend for travel reimbursement (up to $400) to mitigate such factors.

There are many factors that are intertwined and can lead to enrollment and/or attrition rates. It was critical for our team to make some adjustment without compromising the controlled nature of a randomized trial.

Acknowledgment
The authors wish to acknowledge Huong Le, DPM, MPH, who was the coauthor of the study protocol.

A supervised exercise program for patients with venous leg ulcers has shown improved healing times over compression therapy alone, according to a paper published online on Oct. 27 in the British Journal of Dermatology.

In a parallel group feasibility trial, researchers randomized 39 patients with venous ulcers either to a 12-week program of supervised exercise three times a week plus compression therapy (18 patients), or compression therapy alone (21 patients). The exercise program combined aerobic, resistance, and flexibility exercises.

This group showed a median ulcer healing time of 13 weeks (3.9-52 weeks), compared with 34.7 weeks (4.3-52 weeks) for the compression therapy–only group, although the median ulcer size was similar between the two groups at 12 months. At last follow-up of 12 months, 83% of the ulcers in the exercise group had healed, compared with 60% in the control group (Br J Dermatol. 2017 Oct 27. doi: 10.1111/bjd.16089).

The intervention group had a slightly higher quality of life at baseline, as measured by the EQ-5D utility score, and this difference was maintained throughout the study.

Nearly three-quarters (72%) of the exercise group participants went to all the scheduled exercise sessions, with an overall attendance rate of 79%, which the authors noted was high considering many were old, frail, and had no previous exercise experience.

“This was achieved without employing any specific adherence-enhancing components or provision of behavioral change support, which could have potentially improved attendance rates and the effect of the intervention even further,” wrote Markos Klonizakis, DPhil, from the Centre for Sport and Exercise Science at Sheffield (England) Hallam University, and his coinvestigators.

There were no serious adverse events, and only two exercise-related adverse events in the intervention group – both excessive discharge from the ulcer – which resulted in postponement of the exercise sessions for those two individuals.

The exercise regimen was associated with modest reductions in weight, while those in the control group showed an overall increase in weight.

Researchers also assessed the relative costs of the two interventions by getting participants to keep a diary of their use of National Health Service resources, health care visits, prescriptions, and other out-of-pocket expenses.

They calculated that the total mean National Health Service cost per participant for the exercise intervention was £813.27, and £2,298.57 for the control group who received compression therapy only.

The investigators noted that their initial plan had been met with some skepticism from clinicians and patients, some of whom felt that exercise would have a detrimental rather than positive effect on venous ulcer healing.

“Our results suggest that there may be significant potential benefit in healing rates and that, if this were confirmed in a full trial, the introduction of supervised exercise for venous leg ulcers may well also be cost-saving for the National Health Service.”

The study was funded by the National Institute for Health Research. No conflicts of interest were declared.

A supervised exercise program for patients with venous leg ulcers has shown improved healing times over compression therapy alone, according to a paper published online on Oct. 27 in the British Journal of Dermatology.

In a parallel group feasibility trial, researchers randomized 39 patients with venous ulcers either to a 12-week program of supervised exercise three times a week plus compression therapy (18 patients), or compression therapy alone (21 patients). The exercise program combined aerobic, resistance, and flexibility exercises.

This group showed a median ulcer healing time of 13 weeks (3.9-52 weeks), compared with 34.7 weeks (4.3-52 weeks) for the compression therapy–only group, although the median ulcer size was similar between the two groups at 12 months. At last follow-up of 12 months, 83% of the ulcers in the exercise group had healed, compared with 60% in the control group (Br J Dermatol. 2017 Oct 27. doi: 10.1111/bjd.16089).

The intervention group had a slightly higher quality of life at baseline, as measured by the EQ-5D utility score, and this difference was maintained throughout the study.

Nearly three-quarters (72%) of the exercise group participants went to all the scheduled exercise sessions, with an overall attendance rate of 79%, which the authors noted was high considering many were old, frail, and had no previous exercise experience.

“This was achieved without employing any specific adherence-enhancing components or provision of behavioral change support, which could have potentially improved attendance rates and the effect of the intervention even further,” wrote Markos Klonizakis, DPhil, from the Centre for Sport and Exercise Science at Sheffield (England) Hallam University, and his coinvestigators.

There were no serious adverse events, and only two exercise-related adverse events in the intervention group – both excessive discharge from the ulcer – which resulted in postponement of the exercise sessions for those two individuals.

The exercise regimen was associated with modest reductions in weight, while those in the control group showed an overall increase in weight.

Researchers also assessed the relative costs of the two interventions by getting participants to keep a diary of their use of National Health Service resources, health care visits, prescriptions, and other out-of-pocket expenses.

They calculated that the total mean National Health Service cost per participant for the exercise intervention was £813.27, and £2,298.57 for the control group who received compression therapy only.

The investigators noted that their initial plan had been met with some skepticism from clinicians and patients, some of whom felt that exercise would have a detrimental rather than positive effect on venous ulcer healing.

“Our results suggest that there may be significant potential benefit in healing rates and that, if this were confirmed in a full trial, the introduction of supervised exercise for venous leg ulcers may well also be cost-saving for the National Health Service.”

The study was funded by the National Institute for Health Research. No conflicts of interest were declared.

A supervised exercise program for patients with venous leg ulcers has shown improved healing times over compression therapy alone, according to a paper published online on Oct. 27 in the British Journal of Dermatology.

In a parallel group feasibility trial, researchers randomized 39 patients with venous ulcers either to a 12-week program of supervised exercise three times a week plus compression therapy (18 patients), or compression therapy alone (21 patients). The exercise program combined aerobic, resistance, and flexibility exercises.

This group showed a median ulcer healing time of 13 weeks (3.9-52 weeks), compared with 34.7 weeks (4.3-52 weeks) for the compression therapy–only group, although the median ulcer size was similar between the two groups at 12 months. At last follow-up of 12 months, 83% of the ulcers in the exercise group had healed, compared with 60% in the control group (Br J Dermatol. 2017 Oct 27. doi: 10.1111/bjd.16089).

The intervention group had a slightly higher quality of life at baseline, as measured by the EQ-5D utility score, and this difference was maintained throughout the study.

Nearly three-quarters (72%) of the exercise group participants went to all the scheduled exercise sessions, with an overall attendance rate of 79%, which the authors noted was high considering many were old, frail, and had no previous exercise experience.

“This was achieved without employing any specific adherence-enhancing components or provision of behavioral change support, which could have potentially improved attendance rates and the effect of the intervention even further,” wrote Markos Klonizakis, DPhil, from the Centre for Sport and Exercise Science at Sheffield (England) Hallam University, and his coinvestigators.

There were no serious adverse events, and only two exercise-related adverse events in the intervention group – both excessive discharge from the ulcer – which resulted in postponement of the exercise sessions for those two individuals.

The exercise regimen was associated with modest reductions in weight, while those in the control group showed an overall increase in weight.

Researchers also assessed the relative costs of the two interventions by getting participants to keep a diary of their use of National Health Service resources, health care visits, prescriptions, and other out-of-pocket expenses.

They calculated that the total mean National Health Service cost per participant for the exercise intervention was £813.27, and £2,298.57 for the control group who received compression therapy only.

The investigators noted that their initial plan had been met with some skepticism from clinicians and patients, some of whom felt that exercise would have a detrimental rather than positive effect on venous ulcer healing.

“Our results suggest that there may be significant potential benefit in healing rates and that, if this were confirmed in a full trial, the introduction of supervised exercise for venous leg ulcers may well also be cost-saving for the National Health Service.”

The study was funded by the National Institute for Health Research. No conflicts of interest were declared.

The use of topical timolol maleate as a treatment for chronic diabetic and chronic venous ulcers showed increased wound healing compared with controls, according to the results of a prospective observational study of 60 patients.

In the treatment group, 30 patients with chronic leg ulcer (15 diabetic ulcers; 15 venous) received topical application of 0.5% timolol maleate (a beta-blocker) plus conventional antibiotic and wound dressing therapy. In the control group, 30 patients (identical split between diabetic and venous ulcers) were treated with conventional therapy alone, according to a report published in the November issue of the Journal of Vascular Surgery: Venous and Lymphatic Disorders.

Elsevier Inc.

[email protected]

The use of topical timolol maleate as a treatment for chronic diabetic and chronic venous ulcers showed increased wound healing compared with controls, according to the results of a prospective observational study of 60 patients.

In the treatment group, 30 patients with chronic leg ulcer (15 diabetic ulcers; 15 venous) received topical application of 0.5% timolol maleate (a beta-blocker) plus conventional antibiotic and wound dressing therapy. In the control group, 30 patients (identical split between diabetic and venous ulcers) were treated with conventional therapy alone, according to a report published in the November issue of the Journal of Vascular Surgery: Venous and Lymphatic Disorders.

Elsevier Inc.

[email protected]

The use of topical timolol maleate as a treatment for chronic diabetic and chronic venous ulcers showed increased wound healing compared with controls, according to the results of a prospective observational study of 60 patients.

In the treatment group, 30 patients with chronic leg ulcer (15 diabetic ulcers; 15 venous) received topical application of 0.5% timolol maleate (a beta-blocker) plus conventional antibiotic and wound dressing therapy. In the control group, 30 patients (identical split between diabetic and venous ulcers) were treated with conventional therapy alone, according to a report published in the November issue of the Journal of Vascular Surgery: Venous and Lymphatic Disorders.

Elsevier Inc.

[email protected]

Practice Gap

For first-year dermatology residents, dermatologic surgeries can present many challenges. Although approximation of wound edges following excision may be intuitive for the experienced surgeon, an early trainee may need some guidance. Infusion of anesthetics can distort the normal skin field or it may be difficult for the patient to remain in the same position for the required period of time; for example, an elderly patient who requires an excision on the posterior aspect of the neck may be unable to assume the same position for the full duration of the procedure. We offer a simple and effective technique for early-learning dermatology residents to improve surgical closures.

The Technique

We propose drawing straight lines using a sterile marking pen perpendicular to the fusiform plane laid out for any simple, intermediate, or complex linear closure (Figure 1). These lines can then be used as scaffolding for the surgical closure (Figure 2). We recommend drawing the lines at the time of initial planning when the site of excision is in the normal anatomic position.

Practice Implications

By creating a sketch with perpendicular lines, approximation of skin edges and surgical closures may become easier for the learning resident. Patients also can rest more comfortably during the procedure, and the overall cosmesis, healing, and outcome of the procedure may improve. The addition of a sterile marking pen to the surgical tray may aide in highlighting faded pen markings for easier visualization after cleansing of the surgical site.

Practice Gap

For first-year dermatology residents, dermatologic surgeries can present many challenges. Although approximation of wound edges following excision may be intuitive for the experienced surgeon, an early trainee may need some guidance. Infusion of anesthetics can distort the normal skin field or it may be difficult for the patient to remain in the same position for the required period of time; for example, an elderly patient who requires an excision on the posterior aspect of the neck may be unable to assume the same position for the full duration of the procedure. We offer a simple and effective technique for early-learning dermatology residents to improve surgical closures.

The Technique

We propose drawing straight lines using a sterile marking pen perpendicular to the fusiform plane laid out for any simple, intermediate, or complex linear closure (Figure 1). These lines can then be used as scaffolding for the surgical closure (Figure 2). We recommend drawing the lines at the time of initial planning when the site of excision is in the normal anatomic position.

Practice Implications

By creating a sketch with perpendicular lines, approximation of skin edges and surgical closures may become easier for the learning resident. Patients also can rest more comfortably during the procedure, and the overall cosmesis, healing, and outcome of the procedure may improve. The addition of a sterile marking pen to the surgical tray may aide in highlighting faded pen markings for easier visualization after cleansing of the surgical site.

Practice Gap

For first-year dermatology residents, dermatologic surgeries can present many challenges. Although approximation of wound edges following excision may be intuitive for the experienced surgeon, an early trainee may need some guidance. Infusion of anesthetics can distort the normal skin field or it may be difficult for the patient to remain in the same position for the required period of time; for example, an elderly patient who requires an excision on the posterior aspect of the neck may be unable to assume the same position for the full duration of the procedure. We offer a simple and effective technique for early-learning dermatology residents to improve surgical closures.

The Technique

We propose drawing straight lines using a sterile marking pen perpendicular to the fusiform plane laid out for any simple, intermediate, or complex linear closure (Figure 1). These lines can then be used as scaffolding for the surgical closure (Figure 2). We recommend drawing the lines at the time of initial planning when the site of excision is in the normal anatomic position.

Practice Implications

By creating a sketch with perpendicular lines, approximation of skin edges and surgical closures may become easier for the learning resident. Patients also can rest more comfortably during the procedure, and the overall cosmesis, healing, and outcome of the procedure may improve. The addition of a sterile marking pen to the surgical tray may aide in highlighting faded pen markings for easier visualization after cleansing of the surgical site.

The Diagnosis: Nonuremic Calciphylaxis

Histopathologic findings revealed ischemic necrosis and a subepidermal blister (Figure 1) with arteriosclerotic changes and fat necrosis. Foci of calcification were noted within the fat lobules. Arterioles within the deeper dermis and subcutis showed thickened hyalinized walls, narrowed lumina, and medial calcification (Figure 2). Multiple sections did not reveal any granulomatous inflammation. Periodic acid-Schiff and Gram stains were negative for fungal and bacterial elements, respectively. No dense neutrophilic infiltrate was seen. Multifocal calcific deposits within fat lobules and vessel walls (endothelium highlighted by the CD31 stain) suggested calciphylaxis.

Laboratory test results revealed a normal white blood cell count, international normalized ratio level of 4 (on warfarin), and an elevated sedimentation rate at 72 mm/h (reference range, 0-20 mm/h). Serum creatinine was 1.1 mg/dL (reference range, 0.6-1.2 mg/dL) and the calcium-phosphorous product was 40.8 mg²/dL (reference range, <55 mg²/dL). Hemoglobin A_1C (glycated hemoglobin) was 8.2% (reference range, 4%-7%). Wound cultures grew Proteus mirabilis sensitive to cefazolin. Acid-fast bacilli and fungal cultures were negative. Computed tomography of the left lower leg without contrast showed no evidence of osteomyelitis. Of note, the popliteal arteries and distal vessels showed moderate vascular calcification.

Histopathology findings as well as a clinical picture of painful ulceration on the distal extremities and uncontrolled diabetes with normal renal function favored a diagnosis of nonuremic calciphylaxis (NUC). The patient was treated with intravenous infusions of sodium thiosulfate 25 mg 3 times weekly and oral cefazolin for superadded bacterial infection. Local wound care included collagenase dressings with light compression. Warfarin was discontinued, as it can worsen calciphylaxis. Complete reepithelialization of the ulcer along with substantial reduction in pain was noted within 4 weeks.

Ulceration of the lower legs is a relatively common condition in the Western world, the prevalence of which increases up to 5% in patients older than 65 years.¹ Of the myriad of causes that lead to ulceration of the distal aspect of the leg, NUC is a rare but known phenomenon. The pathogenesis of NUC is complicated based on theories of derangement of receptor activator of nuclear factor κβ, receptor activator of nuclear factor κβ ligand, and osteoprotegerin, leading to calcium deposits in the media of the arteries.² This deposition precipitates vascular occlusion coupled with ischemic necrosis of the subcutaneous tissue and skin.³ Some of the more common causes of NUC are primary hyperparathyroidism, malignancy, and rheumatoid arthritis. Type 2 diabetes mellitus is a less common cause but often is found in association with NUC, as noted by Nigwekar et al.² According to their study, the laboratory parameters commonly found in NUC included a calcium-phosphorous product greater than 50 mg²/dL and serum creatinine of 1.2 mg/dL or less.²

Our patient displayed these laboratory findings. However, distinguishing NUC from other atypical lower extremity ulcers such as Martorell hypertensive ischemic ulcer, pyoderma gangrenosum, and warfarin necrosis can pose a challenge to the dermatologist. Martorell hypertensive ischemic ulcer is excruciatingly painful and occurs more frequently near the Achilles tendon, responding well to surgical debridement. Histopathologically, medial calcinosis and arteriosclerosis are seen.⁴

Pyoderma gangrenosum is a neutrophilic dermatosis wherein the classical ulcerative variant is painful. It occurs mostly on the pretibial area and worsens after debridement.⁵ Clinically and histopathologically, it is a diagnosis of exclusion in which a dense neutrophilic to mixed lymphocytic infiltrate is seen with necrosis of dermal vessels.⁶ 

Warfarin necrosis is extremely rare, affecting 0.01% to 0.1% of patients on warfarin-derived anticoagulant therapy.⁷ Necrosis occurs mostly on fat-bearing areas such as the breasts, abdomen, and thighs 3 to 5 days after initiating treatment. Histologically, fibrin deposits occlude dermal vessels without perivascular inflammation.⁸

Necrobiosis lipoidica is a rare cutaneous entity seen in 0.3% of diabetic patients.⁹ The exact pathogenesis is unknown; however, microangiopathy in collaboration with cross-linking of abnormal collagen fibers play a role. These lesions appear as erythematous plaques with a slightly depressed to atrophic center, ultimately taking on a waxy porcelain appearance. Although most of these lesions either resolve or become chronically persistent, approximately 15% undergo ulceration, which can be painful. Histologically, with hematoxylin and eosin staining, areas of necrobiosis are seen surrounded by an inflammatory infiltrate comprised mainly of histiocytes along with lymphocytes and plasma cells.⁹

Nonuremic calciphylaxis can mimic the aforementioned conditions to a greater extent in female patients with obesity, diabetes mellitus, and hypertension. However, microscopic calcium deposition in the media of dermal arterioles, extravascular calcification within fat lobules, and cutaneous necrosis, along with remarkable response to intravenous sodium thiosulfate, confirmed a diagnosis of NUC in our patient. Sodium thiosulfate scavenges reactive oxygen species and promotes nitric oxygen generation, thereby reducing endothelial damage.¹⁰ Although there are no randomized controlled trials to support its use, sodium thiosulfate has been successfully used to treat established cases of NUC.¹¹

The Diagnosis: Nonuremic Calciphylaxis

Histopathologic findings revealed ischemic necrosis and a subepidermal blister (Figure 1) with arteriosclerotic changes and fat necrosis. Foci of calcification were noted within the fat lobules. Arterioles within the deeper dermis and subcutis showed thickened hyalinized walls, narrowed lumina, and medial calcification (Figure 2). Multiple sections did not reveal any granulomatous inflammation. Periodic acid-Schiff and Gram stains were negative for fungal and bacterial elements, respectively. No dense neutrophilic infiltrate was seen. Multifocal calcific deposits within fat lobules and vessel walls (endothelium highlighted by the CD31 stain) suggested calciphylaxis.

Laboratory test results revealed a normal white blood cell count, international normalized ratio level of 4 (on warfarin), and an elevated sedimentation rate at 72 mm/h (reference range, 0-20 mm/h). Serum creatinine was 1.1 mg/dL (reference range, 0.6-1.2 mg/dL) and the calcium-phosphorous product was 40.8 mg²/dL (reference range, <55 mg²/dL). Hemoglobin A_1C (glycated hemoglobin) was 8.2% (reference range, 4%-7%). Wound cultures grew Proteus mirabilis sensitive to cefazolin. Acid-fast bacilli and fungal cultures were negative. Computed tomography of the left lower leg without contrast showed no evidence of osteomyelitis. Of note, the popliteal arteries and distal vessels showed moderate vascular calcification.

Histopathology findings as well as a clinical picture of painful ulceration on the distal extremities and uncontrolled diabetes with normal renal function favored a diagnosis of nonuremic calciphylaxis (NUC). The patient was treated with intravenous infusions of sodium thiosulfate 25 mg 3 times weekly and oral cefazolin for superadded bacterial infection. Local wound care included collagenase dressings with light compression. Warfarin was discontinued, as it can worsen calciphylaxis. Complete reepithelialization of the ulcer along with substantial reduction in pain was noted within 4 weeks.

Ulceration of the lower legs is a relatively common condition in the Western world, the prevalence of which increases up to 5% in patients older than 65 years.¹ Of the myriad of causes that lead to ulceration of the distal aspect of the leg, NUC is a rare but known phenomenon. The pathogenesis of NUC is complicated based on theories of derangement of receptor activator of nuclear factor κβ, receptor activator of nuclear factor κβ ligand, and osteoprotegerin, leading to calcium deposits in the media of the arteries.² This deposition precipitates vascular occlusion coupled with ischemic necrosis of the subcutaneous tissue and skin.³ Some of the more common causes of NUC are primary hyperparathyroidism, malignancy, and rheumatoid arthritis. Type 2 diabetes mellitus is a less common cause but often is found in association with NUC, as noted by Nigwekar et al.² According to their study, the laboratory parameters commonly found in NUC included a calcium-phosphorous product greater than 50 mg²/dL and serum creatinine of 1.2 mg/dL or less.²

Our patient displayed these laboratory findings. However, distinguishing NUC from other atypical lower extremity ulcers such as Martorell hypertensive ischemic ulcer, pyoderma gangrenosum, and warfarin necrosis can pose a challenge to the dermatologist. Martorell hypertensive ischemic ulcer is excruciatingly painful and occurs more frequently near the Achilles tendon, responding well to surgical debridement. Histopathologically, medial calcinosis and arteriosclerosis are seen.⁴

Pyoderma gangrenosum is a neutrophilic dermatosis wherein the classical ulcerative variant is painful. It occurs mostly on the pretibial area and worsens after debridement.⁵ Clinically and histopathologically, it is a diagnosis of exclusion in which a dense neutrophilic to mixed lymphocytic infiltrate is seen with necrosis of dermal vessels.⁶ 

Warfarin necrosis is extremely rare, affecting 0.01% to 0.1% of patients on warfarin-derived anticoagulant therapy.⁷ Necrosis occurs mostly on fat-bearing areas such as the breasts, abdomen, and thighs 3 to 5 days after initiating treatment. Histologically, fibrin deposits occlude dermal vessels without perivascular inflammation.⁸

Necrobiosis lipoidica is a rare cutaneous entity seen in 0.3% of diabetic patients.⁹ The exact pathogenesis is unknown; however, microangiopathy in collaboration with cross-linking of abnormal collagen fibers play a role. These lesions appear as erythematous plaques with a slightly depressed to atrophic center, ultimately taking on a waxy porcelain appearance. Although most of these lesions either resolve or become chronically persistent, approximately 15% undergo ulceration, which can be painful. Histologically, with hematoxylin and eosin staining, areas of necrobiosis are seen surrounded by an inflammatory infiltrate comprised mainly of histiocytes along with lymphocytes and plasma cells.⁹

Nonuremic calciphylaxis can mimic the aforementioned conditions to a greater extent in female patients with obesity, diabetes mellitus, and hypertension. However, microscopic calcium deposition in the media of dermal arterioles, extravascular calcification within fat lobules, and cutaneous necrosis, along with remarkable response to intravenous sodium thiosulfate, confirmed a diagnosis of NUC in our patient. Sodium thiosulfate scavenges reactive oxygen species and promotes nitric oxygen generation, thereby reducing endothelial damage.¹⁰ Although there are no randomized controlled trials to support its use, sodium thiosulfate has been successfully used to treat established cases of NUC.¹¹

The Diagnosis: Nonuremic Calciphylaxis

Histopathologic findings revealed ischemic necrosis and a subepidermal blister (Figure 1) with arteriosclerotic changes and fat necrosis. Foci of calcification were noted within the fat lobules. Arterioles within the deeper dermis and subcutis showed thickened hyalinized walls, narrowed lumina, and medial calcification (Figure 2). Multiple sections did not reveal any granulomatous inflammation. Periodic acid-Schiff and Gram stains were negative for fungal and bacterial elements, respectively. No dense neutrophilic infiltrate was seen. Multifocal calcific deposits within fat lobules and vessel walls (endothelium highlighted by the CD31 stain) suggested calciphylaxis.

Laboratory test results revealed a normal white blood cell count, international normalized ratio level of 4 (on warfarin), and an elevated sedimentation rate at 72 mm/h (reference range, 0-20 mm/h). Serum creatinine was 1.1 mg/dL (reference range, 0.6-1.2 mg/dL) and the calcium-phosphorous product was 40.8 mg²/dL (reference range, <55 mg²/dL). Hemoglobin A_1C (glycated hemoglobin) was 8.2% (reference range, 4%-7%). Wound cultures grew Proteus mirabilis sensitive to cefazolin. Acid-fast bacilli and fungal cultures were negative. Computed tomography of the left lower leg without contrast showed no evidence of osteomyelitis. Of note, the popliteal arteries and distal vessels showed moderate vascular calcification.

Histopathology findings as well as a clinical picture of painful ulceration on the distal extremities and uncontrolled diabetes with normal renal function favored a diagnosis of nonuremic calciphylaxis (NUC). The patient was treated with intravenous infusions of sodium thiosulfate 25 mg 3 times weekly and oral cefazolin for superadded bacterial infection. Local wound care included collagenase dressings with light compression. Warfarin was discontinued, as it can worsen calciphylaxis. Complete reepithelialization of the ulcer along with substantial reduction in pain was noted within 4 weeks.

Ulceration of the lower legs is a relatively common condition in the Western world, the prevalence of which increases up to 5% in patients older than 65 years.¹ Of the myriad of causes that lead to ulceration of the distal aspect of the leg, NUC is a rare but known phenomenon. The pathogenesis of NUC is complicated based on theories of derangement of receptor activator of nuclear factor κβ, receptor activator of nuclear factor κβ ligand, and osteoprotegerin, leading to calcium deposits in the media of the arteries.² This deposition precipitates vascular occlusion coupled with ischemic necrosis of the subcutaneous tissue and skin.³ Some of the more common causes of NUC are primary hyperparathyroidism, malignancy, and rheumatoid arthritis. Type 2 diabetes mellitus is a less common cause but often is found in association with NUC, as noted by Nigwekar et al.² According to their study, the laboratory parameters commonly found in NUC included a calcium-phosphorous product greater than 50 mg²/dL and serum creatinine of 1.2 mg/dL or less.²

Our patient displayed these laboratory findings. However, distinguishing NUC from other atypical lower extremity ulcers such as Martorell hypertensive ischemic ulcer, pyoderma gangrenosum, and warfarin necrosis can pose a challenge to the dermatologist. Martorell hypertensive ischemic ulcer is excruciatingly painful and occurs more frequently near the Achilles tendon, responding well to surgical debridement. Histopathologically, medial calcinosis and arteriosclerosis are seen.⁴

Pyoderma gangrenosum is a neutrophilic dermatosis wherein the classical ulcerative variant is painful. It occurs mostly on the pretibial area and worsens after debridement.⁵ Clinically and histopathologically, it is a diagnosis of exclusion in which a dense neutrophilic to mixed lymphocytic infiltrate is seen with necrosis of dermal vessels.⁶ 

Warfarin necrosis is extremely rare, affecting 0.01% to 0.1% of patients on warfarin-derived anticoagulant therapy.⁷ Necrosis occurs mostly on fat-bearing areas such as the breasts, abdomen, and thighs 3 to 5 days after initiating treatment. Histologically, fibrin deposits occlude dermal vessels without perivascular inflammation.⁸

Necrobiosis lipoidica is a rare cutaneous entity seen in 0.3% of diabetic patients.⁹ The exact pathogenesis is unknown; however, microangiopathy in collaboration with cross-linking of abnormal collagen fibers play a role. These lesions appear as erythematous plaques with a slightly depressed to atrophic center, ultimately taking on a waxy porcelain appearance. Although most of these lesions either resolve or become chronically persistent, approximately 15% undergo ulceration, which can be painful. Histologically, with hematoxylin and eosin staining, areas of necrobiosis are seen surrounded by an inflammatory infiltrate comprised mainly of histiocytes along with lymphocytes and plasma cells.⁹

Nonuremic calciphylaxis can mimic the aforementioned conditions to a greater extent in female patients with obesity, diabetes mellitus, and hypertension. However, microscopic calcium deposition in the media of dermal arterioles, extravascular calcification within fat lobules, and cutaneous necrosis, along with remarkable response to intravenous sodium thiosulfate, confirmed a diagnosis of NUC in our patient. Sodium thiosulfate scavenges reactive oxygen species and promotes nitric oxygen generation, thereby reducing endothelial damage.¹⁰ Although there are no randomized controlled trials to support its use, sodium thiosulfate has been successfully used to treat established cases of NUC.¹¹

SAN DIEGO – Hyperbaric oxygen therapy, a mainstay of wound care, has a long and controversial history as a treatment for diabetic foot ulcers. Conflicting studies have spawned plenty of debate, and the most recent Cochrane Library review of existing research didn’t shed much light on the value of the treatment because the evidence was weak (Cochrane Database Syst Rev. 2015 Jun 24;[6]:CD004123).

But William H. Tettelbach, MD, a wound care specialist, told an audience at the annual scientific sessions of the American Diabetic Association that hyperbaric treatments are worth a try in certain cases. And he brought evidence to prove it – a 2015 report he coauthored that reviewed studies and offered clinical practice guidelines for hyperbaric oxygen therapy for the treatment of diabetic foot ulcers (DFUs) (Undersea Hyperb Med. 2015 May-Jun;42[3]:205-47).

Question: What did your review of research tell you about the value of hyperbaric oxygen treatment for DFUs?

Answer: We came to the same conclusion that most of the papers have indicated over the years: Hyperbaric oxygen is effective and attains goals such as reducing rates of amputation in a select population of diabetic ulcer patients.

Patients who have Wagner grade 3 or greater ulcers or admitted for surgery due to a septic diabetic foot benefit from an evaluation by a hyperbaric medicine–trained physician and treatment when indicated. There is evidence and years of clinical experience indicating that these patients benefit and have improved outcomes when evaluated and treated appropriately with hyperbaric oxygen therapy.

In the United States, hyperbaric oxygen therapy is not indicated in Wagner grade 2, 1 or 0 diabetic foot ulcers, the ulcers that involve soft tissue but not deep structure like bone.
 

Q: Why has there been so much controversy over the value of this treatment? 

A: In the past, there have been problems with commercial outpatient wound centers that are heavily driven by profits. Financial margins in wound care clinics can be tight, and the need to remain profitable has at times resulted in patients being treated inappropriately with hyperbaric oxygen therapy (Adv Skin Wound Care. 2017 Apr;30[4]:181-90).

Q: Why does hyperbaric oxygen treatment work in some cases?

A: When you place a patient in a hyperbaric chamber where they breathe 100% oxygen under pressure, you increase the percentage of oxygen in the blood. At such a high percentage, oxygen saturates the plasma versus just being carried by red blood cells, thereby allowing the oxygen to penetrate farther into hypoxic tissues. By increasing the oxygen, you have the ability to make the environment unfavorable for rapid proliferation of anaerobic or microaerophilic bacteria that do not survive a highly oxygen-rich environment. Increasing tissue oxygen tension to 30 mm Hg or greater increases the macrophages’ ability to have an oxidative burst needed to kill bacteria. Furthermore, there are antibiotics that require certain levels of oxygen for transport across the bacterial cell wall.

Q: What should physicians understand about hyperbaric oxygen therapy for DFUs?

A: Overall, hyperbaric practitioners need to be more selective in identifying and treating patients according to what the evidence supports. Poorly designed trials with misleading results should not drive medical decisions. We should revisit diabetic foot ulcers through well-thought-out studies that target those who would benefit as suggested by current evidence. Prior trials have been heavily weighted with Wagner grade 1 and 2 candidates or ischemic diabetic ulcers that are not revascularized. These are biased toward poor outcomes since the current evidence does not strongly support treating these types of individuals with adjunctive hyperbaric oxygen therapy (Ont Health Technol Assess Ser. 2017 May 12;17[5]:1-142. eCollection 2017).

Q: What conditions should trigger endocrinologists to think about hyperbaric oxygen therapy for their DFU patients?

A: Candidates for the therapy include diabetic ulcers that have persisted for longer than 30 days, since these ulcers are at a significantly higher risk of a complicating infection, along with those that have failed treatment or are becoming more symptomatic over time (Undersea Hyperb Med. 2017 Mar-Apr;44[2]:157-60). 

At that point, it might make sense to refer those patients to a wound and hyperbaric specialist for further evaluation and management, especially to a wound center that offers hyperbaric oxygen therapy.  

These wound centers can be found in smaller towns. But some folks will have to travel, perhaps to a wound center at a hospital that has room and board like they do for cancer patients. 
 

Q: What about treatment after surgery?

A: Using hyperbariatric oxygen therapy to treat inpatients with septic diabetic foot ulcers – Wagner grade 3 or higher – immediately after surgery may reduce length of stay as well as lower the risk of requiring multiple surgical debridements. 

Q: What are the best-case scenarios for treatment?

A: A significant portion of what we do is limb preservation. Hyperbaric oxygen therapy often can help save a digit, forefoot, or even an extremity. 

But it’s not something that just happens overnight. It’s a long-term process. Underlying complicating osteomyelitis may require up to 40-60 adjunctive hyperbaric oxygen treatments, 5 days a week with weekends off, along with concurrent antibiotics, wound care, and vascular interventions when indicated. 
 

Q: Is insurance ever an issue for this treatment?

A: Typically, not if one follows the indications set by the Centers for Medicare & Medicaid Services and the Undersea and Hyperbaric Medical Society.

Medicare lists 15 medical indications that it will cover, and a majority of commercial insurers will cover the same 15 indications and possibly more. But commercial insurers may require prior authorization of medical necessity before preceding with hyperbaric oxygen therapy (Diving Hyperb Med. 2016 Sep;46[3]:133-4).

SAN DIEGO – Hyperbaric oxygen therapy, a mainstay of wound care, has a long and controversial history as a treatment for diabetic foot ulcers. Conflicting studies have spawned plenty of debate, and the most recent Cochrane Library review of existing research didn’t shed much light on the value of the treatment because the evidence was weak (Cochrane Database Syst Rev. 2015 Jun 24;[6]:CD004123).

But William H. Tettelbach, MD, a wound care specialist, told an audience at the annual scientific sessions of the American Diabetic Association that hyperbaric treatments are worth a try in certain cases. And he brought evidence to prove it – a 2015 report he coauthored that reviewed studies and offered clinical practice guidelines for hyperbaric oxygen therapy for the treatment of diabetic foot ulcers (DFUs) (Undersea Hyperb Med. 2015 May-Jun;42[3]:205-47).

Question: What did your review of research tell you about the value of hyperbaric oxygen treatment for DFUs?

Answer: We came to the same conclusion that most of the papers have indicated over the years: Hyperbaric oxygen is effective and attains goals such as reducing rates of amputation in a select population of diabetic ulcer patients.

Patients who have Wagner grade 3 or greater ulcers or admitted for surgery due to a septic diabetic foot benefit from an evaluation by a hyperbaric medicine–trained physician and treatment when indicated. There is evidence and years of clinical experience indicating that these patients benefit and have improved outcomes when evaluated and treated appropriately with hyperbaric oxygen therapy.

In the United States, hyperbaric oxygen therapy is not indicated in Wagner grade 2, 1 or 0 diabetic foot ulcers, the ulcers that involve soft tissue but not deep structure like bone.
 

Q: Why has there been so much controversy over the value of this treatment? 

A: In the past, there have been problems with commercial outpatient wound centers that are heavily driven by profits. Financial margins in wound care clinics can be tight, and the need to remain profitable has at times resulted in patients being treated inappropriately with hyperbaric oxygen therapy (Adv Skin Wound Care. 2017 Apr;30[4]:181-90).

Q: Why does hyperbaric oxygen treatment work in some cases?

A: When you place a patient in a hyperbaric chamber where they breathe 100% oxygen under pressure, you increase the percentage of oxygen in the blood. At such a high percentage, oxygen saturates the plasma versus just being carried by red blood cells, thereby allowing the oxygen to penetrate farther into hypoxic tissues. By increasing the oxygen, you have the ability to make the environment unfavorable for rapid proliferation of anaerobic or microaerophilic bacteria that do not survive a highly oxygen-rich environment. Increasing tissue oxygen tension to 30 mm Hg or greater increases the macrophages’ ability to have an oxidative burst needed to kill bacteria. Furthermore, there are antibiotics that require certain levels of oxygen for transport across the bacterial cell wall.

Q: What should physicians understand about hyperbaric oxygen therapy for DFUs?

A: Overall, hyperbaric practitioners need to be more selective in identifying and treating patients according to what the evidence supports. Poorly designed trials with misleading results should not drive medical decisions. We should revisit diabetic foot ulcers through well-thought-out studies that target those who would benefit as suggested by current evidence. Prior trials have been heavily weighted with Wagner grade 1 and 2 candidates or ischemic diabetic ulcers that are not revascularized. These are biased toward poor outcomes since the current evidence does not strongly support treating these types of individuals with adjunctive hyperbaric oxygen therapy (Ont Health Technol Assess Ser. 2017 May 12;17[5]:1-142. eCollection 2017).

Q: What conditions should trigger endocrinologists to think about hyperbaric oxygen therapy for their DFU patients?

A: Candidates for the therapy include diabetic ulcers that have persisted for longer than 30 days, since these ulcers are at a significantly higher risk of a complicating infection, along with those that have failed treatment or are becoming more symptomatic over time (Undersea Hyperb Med. 2017 Mar-Apr;44[2]:157-60). 

At that point, it might make sense to refer those patients to a wound and hyperbaric specialist for further evaluation and management, especially to a wound center that offers hyperbaric oxygen therapy.  

These wound centers can be found in smaller towns. But some folks will have to travel, perhaps to a wound center at a hospital that has room and board like they do for cancer patients. 
 

Q: What about treatment after surgery?

A: Using hyperbariatric oxygen therapy to treat inpatients with septic diabetic foot ulcers – Wagner grade 3 or higher – immediately after surgery may reduce length of stay as well as lower the risk of requiring multiple surgical debridements. 

Q: What are the best-case scenarios for treatment?

A: A significant portion of what we do is limb preservation. Hyperbaric oxygen therapy often can help save a digit, forefoot, or even an extremity. 

But it’s not something that just happens overnight. It’s a long-term process. Underlying complicating osteomyelitis may require up to 40-60 adjunctive hyperbaric oxygen treatments, 5 days a week with weekends off, along with concurrent antibiotics, wound care, and vascular interventions when indicated. 
 

Q: Is insurance ever an issue for this treatment?

A: Typically, not if one follows the indications set by the Centers for Medicare & Medicaid Services and the Undersea and Hyperbaric Medical Society.

Medicare lists 15 medical indications that it will cover, and a majority of commercial insurers will cover the same 15 indications and possibly more. But commercial insurers may require prior authorization of medical necessity before preceding with hyperbaric oxygen therapy (Diving Hyperb Med. 2016 Sep;46[3]:133-4).

SAN DIEGO – Hyperbaric oxygen therapy, a mainstay of wound care, has a long and controversial history as a treatment for diabetic foot ulcers. Conflicting studies have spawned plenty of debate, and the most recent Cochrane Library review of existing research didn’t shed much light on the value of the treatment because the evidence was weak (Cochrane Database Syst Rev. 2015 Jun 24;[6]:CD004123).

But William H. Tettelbach, MD, a wound care specialist, told an audience at the annual scientific sessions of the American Diabetic Association that hyperbaric treatments are worth a try in certain cases. And he brought evidence to prove it – a 2015 report he coauthored that reviewed studies and offered clinical practice guidelines for hyperbaric oxygen therapy for the treatment of diabetic foot ulcers (DFUs) (Undersea Hyperb Med. 2015 May-Jun;42[3]:205-47).

Question: What did your review of research tell you about the value of hyperbaric oxygen treatment for DFUs?

Answer: We came to the same conclusion that most of the papers have indicated over the years: Hyperbaric oxygen is effective and attains goals such as reducing rates of amputation in a select population of diabetic ulcer patients.

Patients who have Wagner grade 3 or greater ulcers or admitted for surgery due to a septic diabetic foot benefit from an evaluation by a hyperbaric medicine–trained physician and treatment when indicated. There is evidence and years of clinical experience indicating that these patients benefit and have improved outcomes when evaluated and treated appropriately with hyperbaric oxygen therapy.

In the United States, hyperbaric oxygen therapy is not indicated in Wagner grade 2, 1 or 0 diabetic foot ulcers, the ulcers that involve soft tissue but not deep structure like bone.
 

Q: Why has there been so much controversy over the value of this treatment? 

A: In the past, there have been problems with commercial outpatient wound centers that are heavily driven by profits. Financial margins in wound care clinics can be tight, and the need to remain profitable has at times resulted in patients being treated inappropriately with hyperbaric oxygen therapy (Adv Skin Wound Care. 2017 Apr;30[4]:181-90).

Q: Why does hyperbaric oxygen treatment work in some cases?

A: When you place a patient in a hyperbaric chamber where they breathe 100% oxygen under pressure, you increase the percentage of oxygen in the blood. At such a high percentage, oxygen saturates the plasma versus just being carried by red blood cells, thereby allowing the oxygen to penetrate farther into hypoxic tissues. By increasing the oxygen, you have the ability to make the environment unfavorable for rapid proliferation of anaerobic or microaerophilic bacteria that do not survive a highly oxygen-rich environment. Increasing tissue oxygen tension to 30 mm Hg or greater increases the macrophages’ ability to have an oxidative burst needed to kill bacteria. Furthermore, there are antibiotics that require certain levels of oxygen for transport across the bacterial cell wall.

Q: What should physicians understand about hyperbaric oxygen therapy for DFUs?

A: Overall, hyperbaric practitioners need to be more selective in identifying and treating patients according to what the evidence supports. Poorly designed trials with misleading results should not drive medical decisions. We should revisit diabetic foot ulcers through well-thought-out studies that target those who would benefit as suggested by current evidence. Prior trials have been heavily weighted with Wagner grade 1 and 2 candidates or ischemic diabetic ulcers that are not revascularized. These are biased toward poor outcomes since the current evidence does not strongly support treating these types of individuals with adjunctive hyperbaric oxygen therapy (Ont Health Technol Assess Ser. 2017 May 12;17[5]:1-142. eCollection 2017).

Q: What conditions should trigger endocrinologists to think about hyperbaric oxygen therapy for their DFU patients?

A: Candidates for the therapy include diabetic ulcers that have persisted for longer than 30 days, since these ulcers are at a significantly higher risk of a complicating infection, along with those that have failed treatment or are becoming more symptomatic over time (Undersea Hyperb Med. 2017 Mar-Apr;44[2]:157-60). 

At that point, it might make sense to refer those patients to a wound and hyperbaric specialist for further evaluation and management, especially to a wound center that offers hyperbaric oxygen therapy.  

These wound centers can be found in smaller towns. But some folks will have to travel, perhaps to a wound center at a hospital that has room and board like they do for cancer patients. 
 

Q: What about treatment after surgery?

A: Using hyperbariatric oxygen therapy to treat inpatients with septic diabetic foot ulcers – Wagner grade 3 or higher – immediately after surgery may reduce length of stay as well as lower the risk of requiring multiple surgical debridements. 

Q: What are the best-case scenarios for treatment?

A: A significant portion of what we do is limb preservation. Hyperbaric oxygen therapy often can help save a digit, forefoot, or even an extremity. 

But it’s not something that just happens overnight. It’s a long-term process. Underlying complicating osteomyelitis may require up to 40-60 adjunctive hyperbaric oxygen treatments, 5 days a week with weekends off, along with concurrent antibiotics, wound care, and vascular interventions when indicated. 
 

Q: Is insurance ever an issue for this treatment?

A: Typically, not if one follows the indications set by the Centers for Medicare & Medicaid Services and the Undersea and Hyperbaric Medical Society.

Medicare lists 15 medical indications that it will cover, and a majority of commercial insurers will cover the same 15 indications and possibly more. But commercial insurers may require prior authorization of medical necessity before preceding with hyperbaric oxygen therapy (Diving Hyperb Med. 2016 Sep;46[3]:133-4).

The flexible scalpel blade (FSB) is a 2-sided handheld razor blade that serves as a pivotal instrument in certain dermatologic procedures. Its unrivaled sharpness¹ permits pinpoint precision for shave biopsies, excisions of superficial lesions,² scar contouring, and harvesting of split-thickness skin grafts.³ Given its flexibility and long edge, considerable manual dexterity and skill are required to maximize its full potential.

Practice Gap

Prior to practicing on live patients, students on clinical rotation would benefit from in vitro skin simulators to practice correct hand position, FSB control for concave and convex surface cutting, and safety. Prior practice models have included mannequins, tomatoes, and eggplants^.4,5 Here, the authors recommend the use of a banana (genus Musa). In addition to its year-round availability, economic feasibility, simplicity, and portability, the banana has colored skin that well represents the epidermis, dermis, and subcutaneous tissue, allowing for visual feedback. Furthermore, its contour irregularities simulate convexities and concavities for various anatomic locations. Although the firmness of a yellow-green banana provides immediate tissue feedback, the softness and pliability of a ripe banana simulates the consistency of older skin and the use of appropriate traction.

Tools

To begin, one simply requires a marking pen, banana, and razor blade. Various shapes, including a circle, ellipse, rectangle, trapezoid, triangle, and multilobed lesion are demarcated by students or attendings (Figure 1). Careful removal of the pieces helps students improve dexterity, develop feel for the entire edge of the razor blade, and acquire muscle memory for these skilled movements (Figure 2). Three-dimensional spatial reasoning is honed with practice using the FSB to control appropriate thickness and defect depth while creating a smooth bevel around the entire perimeter, which is important for optimal cosmesis in second intention healing or grafting. The shallower the defect created, the faster the healing and the greater the reduction in contracture. Although downward pressure is important to prevent buttonholing or tearing of the tissue being removed, the angle of the blade relative to the tissue must be assessed at all points, and the alteration in color and fiber orientation signify change in depth of the banana peel.

The Technique

To handle the FSB, one can hold the lateral edges of the blade between the thumb and index finger or between the thumb and middle finger. The thumb and index finger position allows for additional flexible working space and visualization, increased traction by the remaining 3 fingers, and greater ease of removal of lesions with considerable height. The thumb and middle finger hold allows for versatile use of the index finger of the same hand for stabilizing the center of the blade, fixing the tissue on the FSB while it is removed, and sliding the specimen off the FSB. It is important to maintain a fixed distance from the blade to the metacarpals at all times to ensure smooth advancement of the blade and visualization. Beginners can lift the pinky finger of the hand holding the FSB and move the finger up and down to control the angle of the blade.

Practice Implications

Generally, we utilize various techniques of shaving using the FSB. We approach the target lesion 2 to 3 mm from the marked location and slide parallel to the skin surface and perpendicular to the lesion until the epidermis is penetrated. Second, we advance the blade toward the lesion with careful attention paid to the perimeter of the lesion and the points of contact of the FSB. For lesions with hardier consistencies, a sawing motion of the blade is employed, which also requires controlled tilting of the wrist to maintain an even depth and smooth bevel. To cut deeper, flexing the FSB with lateral pressure is helpful. More shallow lesions require the instrument to be flatter and less bowed. When finishing the shave, it is important to start angling the blade upward early, either at the center of the targeted lesion or 2 to 3 mm before the demarcated edge of the skin graft, while applying traction away from the lesion and slight downward pressure with the nondominant hand.

For larger lesions, the perimeter may be more difficult to remove precisely and can be achieved by rotating the blade around the lesion with focus on one point of contact of the FSB to cut and glide through the tissue’s perimeter. To achieve a more exact wound edge and to preclude jagged borders, a No. 15 blade can be used to score the perimeter very superficially to the papillary dermis prior to shave removal. The main disadvantage, however, is that the beveled edge is removed.

In summary, the FSB is an exceptional tool for biopsies, tumor removal, scar contouring, and split-thickness skin grafts. Through the banana practice model, one can attain fine control and reap the benefits of the FSB after meticulous and dedicated training.

The flexible scalpel blade (FSB) is a 2-sided handheld razor blade that serves as a pivotal instrument in certain dermatologic procedures. Its unrivaled sharpness¹ permits pinpoint precision for shave biopsies, excisions of superficial lesions,² scar contouring, and harvesting of split-thickness skin grafts.³ Given its flexibility and long edge, considerable manual dexterity and skill are required to maximize its full potential.

Practice Gap

Prior to practicing on live patients, students on clinical rotation would benefit from in vitro skin simulators to practice correct hand position, FSB control for concave and convex surface cutting, and safety. Prior practice models have included mannequins, tomatoes, and eggplants^.4,5 Here, the authors recommend the use of a banana (genus Musa). In addition to its year-round availability, economic feasibility, simplicity, and portability, the banana has colored skin that well represents the epidermis, dermis, and subcutaneous tissue, allowing for visual feedback. Furthermore, its contour irregularities simulate convexities and concavities for various anatomic locations. Although the firmness of a yellow-green banana provides immediate tissue feedback, the softness and pliability of a ripe banana simulates the consistency of older skin and the use of appropriate traction.

Tools

To begin, one simply requires a marking pen, banana, and razor blade. Various shapes, including a circle, ellipse, rectangle, trapezoid, triangle, and multilobed lesion are demarcated by students or attendings (Figure 1). Careful removal of the pieces helps students improve dexterity, develop feel for the entire edge of the razor blade, and acquire muscle memory for these skilled movements (Figure 2). Three-dimensional spatial reasoning is honed with practice using the FSB to control appropriate thickness and defect depth while creating a smooth bevel around the entire perimeter, which is important for optimal cosmesis in second intention healing or grafting. The shallower the defect created, the faster the healing and the greater the reduction in contracture. Although downward pressure is important to prevent buttonholing or tearing of the tissue being removed, the angle of the blade relative to the tissue must be assessed at all points, and the alteration in color and fiber orientation signify change in depth of the banana peel.

The Technique

To handle the FSB, one can hold the lateral edges of the blade between the thumb and index finger or between the thumb and middle finger. The thumb and index finger position allows for additional flexible working space and visualization, increased traction by the remaining 3 fingers, and greater ease of removal of lesions with considerable height. The thumb and middle finger hold allows for versatile use of the index finger of the same hand for stabilizing the center of the blade, fixing the tissue on the FSB while it is removed, and sliding the specimen off the FSB. It is important to maintain a fixed distance from the blade to the metacarpals at all times to ensure smooth advancement of the blade and visualization. Beginners can lift the pinky finger of the hand holding the FSB and move the finger up and down to control the angle of the blade.

Practice Implications

Generally, we utilize various techniques of shaving using the FSB. We approach the target lesion 2 to 3 mm from the marked location and slide parallel to the skin surface and perpendicular to the lesion until the epidermis is penetrated. Second, we advance the blade toward the lesion with careful attention paid to the perimeter of the lesion and the points of contact of the FSB. For lesions with hardier consistencies, a sawing motion of the blade is employed, which also requires controlled tilting of the wrist to maintain an even depth and smooth bevel. To cut deeper, flexing the FSB with lateral pressure is helpful. More shallow lesions require the instrument to be flatter and less bowed. When finishing the shave, it is important to start angling the blade upward early, either at the center of the targeted lesion or 2 to 3 mm before the demarcated edge of the skin graft, while applying traction away from the lesion and slight downward pressure with the nondominant hand.

For larger lesions, the perimeter may be more difficult to remove precisely and can be achieved by rotating the blade around the lesion with focus on one point of contact of the FSB to cut and glide through the tissue’s perimeter. To achieve a more exact wound edge and to preclude jagged borders, a No. 15 blade can be used to score the perimeter very superficially to the papillary dermis prior to shave removal. The main disadvantage, however, is that the beveled edge is removed.

In summary, the FSB is an exceptional tool for biopsies, tumor removal, scar contouring, and split-thickness skin grafts. Through the banana practice model, one can attain fine control and reap the benefits of the FSB after meticulous and dedicated training.

The flexible scalpel blade (FSB) is a 2-sided handheld razor blade that serves as a pivotal instrument in certain dermatologic procedures. Its unrivaled sharpness¹ permits pinpoint precision for shave biopsies, excisions of superficial lesions,² scar contouring, and harvesting of split-thickness skin grafts.³ Given its flexibility and long edge, considerable manual dexterity and skill are required to maximize its full potential.

Practice Gap

Prior to practicing on live patients, students on clinical rotation would benefit from in vitro skin simulators to practice correct hand position, FSB control for concave and convex surface cutting, and safety. Prior practice models have included mannequins, tomatoes, and eggplants^.4,5 Here, the authors recommend the use of a banana (genus Musa). In addition to its year-round availability, economic feasibility, simplicity, and portability, the banana has colored skin that well represents the epidermis, dermis, and subcutaneous tissue, allowing for visual feedback. Furthermore, its contour irregularities simulate convexities and concavities for various anatomic locations. Although the firmness of a yellow-green banana provides immediate tissue feedback, the softness and pliability of a ripe banana simulates the consistency of older skin and the use of appropriate traction.

Tools

To begin, one simply requires a marking pen, banana, and razor blade. Various shapes, including a circle, ellipse, rectangle, trapezoid, triangle, and multilobed lesion are demarcated by students or attendings (Figure 1). Careful removal of the pieces helps students improve dexterity, develop feel for the entire edge of the razor blade, and acquire muscle memory for these skilled movements (Figure 2). Three-dimensional spatial reasoning is honed with practice using the FSB to control appropriate thickness and defect depth while creating a smooth bevel around the entire perimeter, which is important for optimal cosmesis in second intention healing or grafting. The shallower the defect created, the faster the healing and the greater the reduction in contracture. Although downward pressure is important to prevent buttonholing or tearing of the tissue being removed, the angle of the blade relative to the tissue must be assessed at all points, and the alteration in color and fiber orientation signify change in depth of the banana peel.

The Technique

To handle the FSB, one can hold the lateral edges of the blade between the thumb and index finger or between the thumb and middle finger. The thumb and index finger position allows for additional flexible working space and visualization, increased traction by the remaining 3 fingers, and greater ease of removal of lesions with considerable height. The thumb and middle finger hold allows for versatile use of the index finger of the same hand for stabilizing the center of the blade, fixing the tissue on the FSB while it is removed, and sliding the specimen off the FSB. It is important to maintain a fixed distance from the blade to the metacarpals at all times to ensure smooth advancement of the blade and visualization. Beginners can lift the pinky finger of the hand holding the FSB and move the finger up and down to control the angle of the blade.

Practice Implications

Generally, we utilize various techniques of shaving using the FSB. We approach the target lesion 2 to 3 mm from the marked location and slide parallel to the skin surface and perpendicular to the lesion until the epidermis is penetrated. Second, we advance the blade toward the lesion with careful attention paid to the perimeter of the lesion and the points of contact of the FSB. For lesions with hardier consistencies, a sawing motion of the blade is employed, which also requires controlled tilting of the wrist to maintain an even depth and smooth bevel. To cut deeper, flexing the FSB with lateral pressure is helpful. More shallow lesions require the instrument to be flatter and less bowed. When finishing the shave, it is important to start angling the blade upward early, either at the center of the targeted lesion or 2 to 3 mm before the demarcated edge of the skin graft, while applying traction away from the lesion and slight downward pressure with the nondominant hand.

For larger lesions, the perimeter may be more difficult to remove precisely and can be achieved by rotating the blade around the lesion with focus on one point of contact of the FSB to cut and glide through the tissue’s perimeter. To achieve a more exact wound edge and to preclude jagged borders, a No. 15 blade can be used to score the perimeter very superficially to the papillary dermis prior to shave removal. The main disadvantage, however, is that the beveled edge is removed.

In summary, the FSB is an exceptional tool for biopsies, tumor removal, scar contouring, and split-thickness skin grafts. Through the banana practice model, one can attain fine control and reap the benefits of the FSB after meticulous and dedicated training.

NEW ORLEANS – An oral antibiotic in development in the United States, fusidic acid (oral formulation, sodium fusidate) was noninferior to linezolid based on early clinical response in a randomized, double-blind, multicenter trial of 716 people with acute bacterial skin and skin structure infections (ABSSSI), including cellulitis, wound infection, and major cutaneous abscesses.

Early clinical response was defined as a 20% or greater reduction from baseline in the surface area of redness, edema, or induration at 48-72 hours after starting treatment with the study drugs. In an intent-to-treat analysis, 87.2% of patients randomized to fusidic acid and 86.6% of the linezolid group met this primary endpoint of the phase 3 study.

[email protected]

NEW ORLEANS – An oral antibiotic in development in the United States, fusidic acid (oral formulation, sodium fusidate) was noninferior to linezolid based on early clinical response in a randomized, double-blind, multicenter trial of 716 people with acute bacterial skin and skin structure infections (ABSSSI), including cellulitis, wound infection, and major cutaneous abscesses.

Early clinical response was defined as a 20% or greater reduction from baseline in the surface area of redness, edema, or induration at 48-72 hours after starting treatment with the study drugs. In an intent-to-treat analysis, 87.2% of patients randomized to fusidic acid and 86.6% of the linezolid group met this primary endpoint of the phase 3 study.

[email protected]

NEW ORLEANS – An oral antibiotic in development in the United States, fusidic acid (oral formulation, sodium fusidate) was noninferior to linezolid based on early clinical response in a randomized, double-blind, multicenter trial of 716 people with acute bacterial skin and skin structure infections (ABSSSI), including cellulitis, wound infection, and major cutaneous abscesses.

Early clinical response was defined as a 20% or greater reduction from baseline in the surface area of redness, edema, or induration at 48-72 hours after starting treatment with the study drugs. In an intent-to-treat analysis, 87.2% of patients randomized to fusidic acid and 86.6% of the linezolid group met this primary endpoint of the phase 3 study.

[email protected]