Werner, Sabine, and Richard Grose. Regulation of Wound Healing by Growth Factors and Cytokines. Physiol Rev 83: 835–870, 2003; 10.1152/physrev.00032.2002.—Cutaneous wound healing is a complex proce...

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Regulation of Wound Healing by Growth Factors and Cytokines

This review focuses on calcium phosphate-based bone substitute materials that are used (or can be used) for teeth or bone replacement, bone repair, augmentation, or regeneration. This review will also include some properties of bone (e.g., interconnected porosity, biodegradability, bioactivity, osteoconductivity) that are being mimicked in the manufacture of calcium phosphate-based biomaterials and some of the reported factors and strategies that can make the calcium phosphate-based biomaterials acquire osteoinductive properties. Archaeological findings showed that attempts to replace missing teeth date back to the prehistoric period. The materials used then included shells, corals, ivory (from elephant tusks), metals, and human (from corpses) and animal bones. Because of the practice of cremation in many societies, not much is known about prehistoric materials used to replace bones lost to accident or disease. Presently, autografts (bones obtained from another anatomic site in the same subject) remain the gold standard for bone repair, substitution, and augmentation followed by allografts (bones from another subject, such as processed cadaver bones). Autografts and allografts while having the important advantage of being osteogenic or osteoinductive (i.e., inducing bone formation), suffer from several disadvantages. With autografts the drawbacks include additional expense and trauma to the patient, possibility of donor site morbidity, and limited availability. In the case of allografts, in addition to limited supply and high cost, potential viral transmission and immunogenicity are of serious concern. Because of the high cost and limited availability of autografts and allografts, there is a great need to develop synthetic alternative biomaterials for bone replacement, repair, and augmentation. Current commercial substitute materials to replace or repair teeth and bones include metals, polymers (natural or synthetic), corals, human bones (processed cadaver bones), animal bones (processed cow bones), corals and coral derived, synthetic ceramics (calcium phosphates, calcium sulfates, calcium carbonate, bioactive glasses), and composites. It is interesting to note that several of the materials used in prehistoric times are similar to the materials used presently (e.g., coral and coral derived, animal bone derived, metals). Generally, depending on the ability to stimulate bone tissue, materials for tooth or bone repair or replacement are classified as bioinert or bioactive. Bioinert materials do not stimulate bone formation but instead stimulate formation of fibrous tissue and therefore do not directly bond to bone and thus form a weak biomaterial-bone interface. Bioactive materials stimulate bone tissue formation and therefore directly bond with bone and thus form a uniquely strong biomaterial-bone interface. Bioinert materials include metals (e.g., titanium or titanium alloys, stainless steel, cobalt-chromium, Co-Cr, alloys), some synthetic polymers (e.g., PEEK, Teflon-type), and some ceramics (e.g., alumina, * To whom correspondence should be addressed. Phone: (212) 998-9580. Fax: (212) 995-4244. E-mail: rzl1@nyu.edu. Racquel Zapanta LeGeros received her Ph.D. degree from New York University. She is currently a Professor and Associate Chair of the Department of Biomaterials and Biomimetics at New York University College of Dentistry. Her pioneering work was on substitution in the apatite structure and effect on properties. Her research interests includes biologic and synthetic apatites and related calcium phosphates, calcium phosphatebased biomaterials in the form of granules, scaffolds, cements, and coatings, and implant surface modifications. Her current research is on the development of calcium phosphate-based biomaterial for prevention of bone loss induced by diseases (e.g., osteoporosis), therapy (e.g., radiation), condition (e.g., mineral deficiency, immobility), and recovery of bone loss. She is married to Dr. John P. LeGeros and mother of Bernard, David, Katherine, and Alessandra. Chem. Rev. 2008, 108, 4742–4753 4742

Calcium phosphate-based osteoinductive materials.

Bioceramics of calcium orthophosphates

https://www.jidonline.org/article/S0022-202X(15)33382-0/pdf

Keratinocyte–Fibroblast Interactions in Wound Healing

Adult bone marrow derived mesenchymal stem cells offer the potential to open a new frontier in medicine. Regenerative medicine aims to replace effete cells in a broad range of conditions associated with damaged cartilage, bone, muscle, tendon and ligament. However the normal process of immune rejection of mismatched allogeneic tissue would appear to prevent the realisation of such ambitions. In fact mesenchymal stem cells avoid allogeneic rejection in humans and in animal models. These finding are supported by in vitro co-culture studies. Three broad mechanisms contribute to this effect. Firstly, mesenchymal stem cells are hypoimmunogenic, often lacking MHC-II and costimulatory molecule expression. Secondly, these stem cells prevent T cell responses indirectly through modulation of dendritic cells and directly by disrupting NK as well as CD8+ and CD4+ T cell function. Thirdly, mesenchymal stem cells induce a suppressive local microenvironment through the production of prostaglandins and interleukin-10 as well as by the expression of indoleamine 2,3,-dioxygenase, which depletes the local milieu of tryptophan. Comparison is made to maternal tolerance of the fetal allograft, and contrasted with the immune evasion mechanisms of tumor cells. Mesenchymal stem cells are a highly regulated self-renewing population of cells with potent mechanisms to avoid allogeneic rejection.

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Mesenchymal stem cells avoid allogeneic rejection

One of the specific skin lesions occurring after Bacille Calmette-Guerin (BCG) vaccination is generalized tuberculid-like eruptions, which occur rarely, but have a tendency to heal spontaneously. Their pathogenesis and relationship to "true" tuberculids are poorly understood. This report presents a case of a 6-month-old girl who developed generalized papulonecrotic tuberculid-like eruptions after BCG vaccination. The skin lesions healed spontaneously in 3 months. Culture of blood, gastric juice and reverse transcription polymerase chain reaction (RT-PCR) of papulonecrotic skin biopsies were all negative for Mycobacterium tuberculosis. Histopathology of papulonecrotic eruptions revealed marked epidermal necrosis, perivascular lymphocytic infiltrates and epidermotropic infiltration of lymphocytes showing markers of CD3(+) lymphocytes (90-95% of all infiltrating cells), CD4(+) (40-50%), CD8(+) (40-50%), and CD45RO(+) (70%). In contrast, the BCG vaccination site revealed intradermal granuloma with epithelioid cells, occasional giant cells and infiltration of lymphocytes consisting of CD3(+) (60-70%), CD4(+) (40-50%), CD8(+) (30-40%), CD45RO(+) (40%), CD79a(+) (30-40%), and CD20(+) (20-30%). Our patient did not reveal any signs indicative of tuberculosis. Papulonecrotic lesions were therefore called papulonecrotic tuberculid-like eruptions, rather than tuberculids, that occurred after BCG vaccination and appeared to derive from a hypersensitive reaction mediated by immune lymphocytic infiltration.

Papulonecrotic tuberculid‐like eruptions after Bacille Calmette‐Guerin vaccination

Based on helical volume scan computed tomography (HVCT) data, it has been demonstrated previously that real-size models can be prepared with the binder-jet method with extremely high precision of various parts ranging from the outer structure of the cranio-maxillofacial bone to such fine parts as the cranial base and the orbital walls. The application of this method to clinical cases with large cranial bone defects has also been studied. The results showed the usefulness of the binder-jet method, employing starch for fixing, with which a model can be prepared faster and with less deformity caused by the weight of the material itself. Therefore, the binder-jet method is expected to attain greater clinical significance in this field.In this study the comparison between the shapes of implants before and after implantation revealed that the most important aspect of the design of hydroxyapatite (HAP) implants was determining the shapes of edges, especially its angles. That is, an implant needs very little trimming before being implanted to the patient's defective site if the shape of the edges of the implant can be designed and prepared to fix the incised bone surfaces properly. In addition, to obtain optimum results it was also shown that it is necessary to design optimal shapes of implants, taking into account thickness, porosity, and curvature, before processing the shapes of edges. It was found necessary to establish a technology and a method for producing HAP implants that perfectly fit cranial bone defects. For this purpose, it would be useful to make a template of the implants using the mirror-reversion and binder-jet methods. © 2002 Wiley Periodicals, Inc. J Biomed Mater Res (Appl Biomater) 63: 312–318, 2002

A comparison of the shapes of hydroxyapatite implants before and after implantation.

Purpose: The usefulness of dissolving microneedles (DMs) for local skin therapy by basic fibroblast growth factor (bFGF) was studied in rats. Methods: We prepared four kinds of bFGF-loaded DMs, approximately 500 μm length and 300 μm diameter at the bottom. Long-term stability and dissolution studies were performed by HPLC method. Pharmacokinetic and pharmacological evaluations were performed after administration of bFGF loaded DMs to rats. Results: The bFGF contents were 2.15 ± 0.07, 1.07 ± 0.04, 0.56 ± 0.07 and 0.12 ± 0.03 μg. The 100.2 ± 3.4%, 100.2 ± 3.3%, 99.3 ± 1.4% and 100.4 ± 3.0% of bFGF were recovered after 1, 3 and 6 months and 1 year incubation at 40°C. The bFGF was released from DMs within 5 min. In a pharmacokinetic study using 2.0 and 1.0 μg bFGF-loaded DMs, no systemic exposure of bFGF was detected. The initial bFGF concentrations in the rat skin tissue after administration of bFGF-loaded DMs to the hair-removed rat abdominal skin were 510.2 ± 20.1 ng/g wet weight for 2 μg bFGF DMs and 264.2 ± 56.5 ng/g wet weight for 1 μg DMs, declining slowly thereafter to 226.3 ± 33.5 and 105.1 ± 27.4 ng/g wet weight at 6 hr after administration. Good dose-dependency was observed. Pharmacological evaluation of bFGF-loaded DMs of 2.0, 1.0, 0.5, and 0.1 μg, in the wound healing rat model, all used DMs, but 0.1 μg DMs, showed good healing effects. Considered collectively, these results suggest the usefulness of bFGF-loaded DMs for local therapy of skin wound disease.

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Usefulness of Basic Fibroblast Growth Factor (bFGF) Loaded Dissolving Microneedles for Local Therapy of Skin Wounds

Etretinate has proven to be effective in the treatment of psoriasis. Since abnormal proliferation and cytokine secretion are well-known features of psoriatic epidermis, we studied the in vitro effects of etretinate on these two processes using human keratinocytes. Etretinate promoted proliferation of normal human keratinocytes (NHKs) grown in keratinocyte growth medium (KGM) but not in growth factor-deficient keratinocyte basic medium (KBM). Moreover, etretinate partly overcame growth inhibition by PMA. Etretinate was shown to have an effect on either IL-1 alpha or IL-8 secretion in unstimulated NHKs. In HSC-1, a human squamous cell carcinoma cell line cultured in 20% FCS/DMEM, inhibited IL-1 alpha secretion and enhanced IL-8 secretion. These results indicate that the effects of etretinate on keratinocyte proliferation and cytokine secretion may depend on cell type and culture conditions. Stimulation of NHKs with PMA significantly enhanced IL-1 alpha and IL-8 secretion, and these effects were inhibited by etretinate. However, etretinate failed to inhibit rTNF alpha-induced IL-8 secretion, suggesting that etretinate regulation of NHK cytokine secretion may also depend on the stimulus. As treatment of keratinocytes or epidermis with PMA can induce psoriasis-like changes, so might the experimental "anti-PMA" activity of etretinate be related to its therapeutic benefit in the treatment of psoriasis.

Effects of Etretinate on Keratinocyte Proliferation and Secretion of Interleukin-1α (IL-1α) and IL-8

Malignant tumors of the lip, including squamous cell carcinoma, occur fairly frequently.1 Wedge excision and suture comprise the method of choice if less than one third of the lip is excised. However, local skin flaps, such as Estlander’s method and the double crosslip flap method, are excellent for reconstruction after excision of malignant tumors of the lower lip, when the excision area extends over the border of a mucosal part.2–6 There are cases in which it seems to be excessive surgery, because normal skin without tumor invasion should be excised to some extent when making the wedge-shaped excision for lower lip reconstruction.7–11 This is especially true when using the latter method,6 since the point that connects both lips after the primary operation requires a second operation, which is a burden for the patient. In addition, reconstruction of the lower lip, particularly the vermilion, is important both aesthetically and functionally after resection of a malignant tumor of this region.12–18 However, it is difficult technically in patients in whom the vermilion defect is wide. In addition to the aesthetic and functional requirements, reconstruction of the lower lip vermilion must ensure that the postoperative acquisition of sensation and sphincter function occurs as early as possible,7,15 a requirement that often makes it difficult to select a satisfactory surgical procedure. In an attempt to solve these problems, we reported previously on the reconstruction of vermilion with a buccal musculomucosal flap.19 In this report, a method that uses a buccal musculomucosal flap for vermilion combined with V-Y plasty of the triangular island flap for lower lip reconstruction is described, and its clinical application is discussed. In 1997 we reported that the buccinator muscle vascularized mucosal flap, the buccal musculomucosal flap,19 sacrifices little tissue for the flap donor because it uses a cheek side musculomucosal flap for the lower vermilion reconstruction and is sutured primarily. This musculomucosal flap, which we devised for reconstruction of the lower lip vermilion, is safe and reliable, because it contains the communicating branch of a lesser palatine artery, a buccal artery, and a facial artery that nourish the buccinator muscle just beneath the mucosa.20–23 A feature of such a 15-mm-wide, 50-mm-long musculomucosal flap is that it can be elevated safely.19 Although this method is extremely useful when pathological changes are limited to the vermilion, it has limitations in cases in which the pathological change that permeated to the lower lip skin exceeds the vermilion border or in cases in which excision of the skin of the lower lip needs to be more than 1 cm from the edge of the vermilion. In this report, a new reconstruction method after excision of a tumor of the lower lip is described. With this method, the lower lip is reconstructed with the triangular island flap designed in accordance with the width of the excision on the lower lip,24 and the defect of the vermilion is then reconstructed using a musculomucosal flap, as reported previously.19 When the width of the excision is narrow, one triangular flap is designed in the middle, and when it is wider, two triangular flaps, each half the width of From the Department of Dermatology, Sapporo Medical University School of Medicine. Received for publication July 8, 2004; revised November 16, 2004. Copyright ©2006 by the American Society of Plastic Surgeons

Ichiro Ono

Papers

Papulonecrotic tuberculid‐like eruptions after Bacille Calmette‐Guerin vaccination

A comparison of the shapes of hydroxyapatite implants before and after implantation.

Usefulness of Basic Fibroblast Growth Factor (bFGF) Loaded Dissolving Microneedles for Local Therapy of Skin Wounds

Effects of Etretinate on Keratinocyte Proliferation and Secretion of Interleukin-1α (IL-1α) and IL-8

Lower lip and vermilion reconstruction with buccal musculomucosal flap combined with V-Y plasty after malignant tumor excision.