Pharmaceuticals & Vitamin D : Skin & connective tissue

Pharmaceuticals & Vitamin D Portfolios


Bioengineered Vocal Fold Mucosa for Voice Restoration

UW–Madison researchers have engineered vocal fold mucosae from isolated and purified human VF fibroblasts and epithelial cells, co-cultured under organotypic conditions. When grafted into larynges ex vivo, the engineered VF mucosae generate vibratory behavior and acoustic output indistinguishable from native VF tissue, thus demonstrating that they have the biomechanical properties essential for use as an implant in treating voice impairment due to tissue damage, loss or disease.

In addition, when grafted into humanized mice in vivo (a transgenic mouse model supporting a functional human adaptive immune system) the mucosae survive and are well tolerated by the human adaptive immune system. This indicates that implanting the engineered mucosa into the larynx of a human patient would likely not trigger rejection or immune system attack against the implant.

More Stable Collagen Mimetic Peptides for Wound Healing

UW–Madison researchers have developed a superior linkage between CMP strands that substantially improves their structural stability. The new linkage uses homocysteine in place of cysteine in one of the strands. The resulting bond reduces strain and can therefore be used to enhance CMP-based biomaterials and enable previously inaccessible molecular designs.

Skin Whitening Agent(s)

Following on from earlier research focused on development of stilbenoid-based derivatives for antimicrobial activity (isolated originally from the sweet fern Comptonia peregrina), researchers at UW-River Falls have generated a preclinical data package using zebrafish embryos which demonstrates lead analogues to possess potent skin-lightening activity. The zebrafish embryo model makes an excellent model for pigmentation studies due to the rapid and well-conserved melanocyte development and melanin synthesis. Lead compound, A11, has been shown to have more potent activity compared to a number of current skin-lightening compounds including arbutin which required a significantly higher concentration (300mM) to achieve comparable effects as A11 at 10M (70% versus 90% inhibition, respectively). Most importantly, A11 caused no detectable toxicity, whereas niaciamide and tretinoin caused strong toxicity to developing embryos while gallic acid killed the embryos at 50mM and arbutin caused cardiac degeneration. When tested for long-term efficacy, A11-incubated embryos demonstrated a 50% recovery of pigment 48 hours after wash, suggesting longer-acting skin-lightening effect as compared to other products which fully recovered (100%) their pigment within 24 hours after wash. Importantly, while A11 possessed these longer-acting effects, this study also demonstrated that the effects are reversible, which is an important factor for skin-whitening agents. Unlike most products on the market, A11 does not appear to act by inhibiting the tyrosinase enzyme and preliminary studies in a melanoma cell line suggest that the molecule may possess a different mechanism of action and may lead to skin-lightening via the control of melanocyte development and/or proliferation. Further studies are underway to better understand the molecular mechanisms of A11 using fish embryo and mouse melanoma cell lines. Interestingly, preliminary data from these studies also support potential use of these compounds in melanoma treatment. Additional in vivo studies utilizing a guinea pig or mouse model has been proposed to further validate the skin-lightening activity of A11 and related analogues.

Click Chemistry-Based Multi-Enhanced Biomaterials Help Heal Wounds

The UW–Madison researchers have now adapted “click chemistry” in lieu of an external energy source to form the sIPNs. This allows a wider variety of sensitive bioactive molecules, including therapeutic cells, to be entrapped within the sIPNs, enhancing the clinical applicability of the technology.

Strong, Stable, Semisynthetic Collagen Mimic for Wound Healing, Artificial Skin, Sutures and Leather

UW-Madison researchers have discovered that the hydroxyl group of Hyp acts primarily through stereoelectronic effects, and that hydration of Hyp residues provides no benefit. As a result, the Hyp residues in collagen can be modified through O-methylation to increase stability.

The inventors replaced the natural Hyp residues in the Yaa position with synthetic, O-methylated (2S,4R)-4-methoxyproline (Mop) residues. This change resulted in a semisynthetic collagen mimic with increased strength and durability. 

Treating Fibrotic Disorders by Inhibiting BMP-1-Like Proteinases

UW-Madison researchers have devleoped a method of treating fibrotic disorders by inhibiting BMP-1-like proteinases. The protein alpha2-macroglobulin (alpha2M), which binds peptides and particles, can be used to inhibit BMP-1-like proteinases. Each subunit of alpha2M includes sites that various proteinases can cleave, activating the alpha2M. The activated alpha2M then forms a covalent complex with the proteinase, inhibiting its proteolytic activities.

The inventors have engineered an alpha2M so that its ability to inhibit BMP-1-like proteinases is enhanced approximately 25-fold. The engineered alpha2M, or a native form, can be administered to a patient to reduce the formation of ECM. The alpha2M may be modified to further enhance its ability to inhibit BMP-1 activity.

Stable Collagen Mimics

UW-Madison researchers have developed several new collagen mimics that use steric, rather than stereoelectronic, effects to achieve increased stability. The collagen mimics consist of a tripeptide unit with the formula (Xaa-Yaa-Gly)n, where either Xaa or Yaa is a bulky, non-electron withdrawing, 4-substituted proline derivative that contains an alkyl or thiol group, and n is a positive integer of at least 3.

Replacing a proline derivative at the Xaa or Yaa position results in steric effects that increase the stability of the helix. Specifically, three collagen variants that are more stable than native collagen are (Pro-Mep-Gly)7, (mep-Pro-Gly)7 and (mep-Mep-Gly)7, where Mep is (2S,4S)-4-methylproline and mep is (2S,4R)-4-methylproline. In addition, a fluoroproline may be substituted at the Xaa or Yaa position to further increase the strength and stability of the collagen.

Use of Neuropeptides for Ligament Healing

UW-Madison researchers have developed a method of using neuropeptides to shorten the healing period and increase the strength of ligaments damaged by traumatic injury, disease or disuse. The researchers demonstrated that several neuropeptides play a role in ligament healing. To treat ligament damage, one or more of these neuropeptides, which include calcitonin gene-related peptide (CGRP), cholecystokinin (CCK), dynorphin, enkephalin, galanin, neuropeptide Y (NPY), neurotensin, somatostatin, substance P (SP), thyrotropin-releasing hormone (TRH) and vasoactive intestinal peptide (VIP), are delivered directly to the damaged ligament. Experiments in rats showed that damaged medial cruciate ligaments (MCLs) treated with the neuropeptides were as strong as or stronger than uninjured MCLs.

Hyperstable Collagen Mimics

UW-Madison researchers have developed a novel, hyperstable collagen mimic. This new collagen mimic consists of a tripeptide unit with the formula (flpYaaGly)n, where flp is 4(S)-fluoroproline, Yaa is any natural or modified amino acid residue, and n is a positive integer, preferably at least 7. The novel compound forms triple helices that are more stable than native collagen.

Modified Retinoid Compounds with Reduced Toxicity

UW-Madison researchers have developed modified retinoid esters with reduced toxicity. The carboxyl group of a retinoid is esterified with a highly sterically hindered compound, preferably a secondary or tertiary alcohol. The resulting retinoid esters are significantly less toxic than the parent retinoids and can be administered orally with minimal side effects.

Multi-Functional Matrix to Promote Wound Healing and for Other Biomedical Applications

Using Biofunctionalized Biomaterials to Recapitulate Tissue Structure Lost Due to Trauma or Underlying Disease to Improve Healing
UW–Madison researchers have developed semi-interpenetrating networks (sIPNs), a platform material that mimics the extracellular matrix and allows delivery of factors like therapeutic cells that promote healing to the wound bed. The sIPNs use a multi-functional hydrogel as a scaffold for damaged tissues. The polymer material consists of a biochemically-modified and cross-linked gelatin matrix, onto which are grafted various heterodifunctional polyethylene glycols (hPEGs). The hPEGs increase the biocompatibility and durability of the hydrogel and also provide attachment sites for therapeutic molecules. The biodegradable matrix allows for temporally and spatially controlled delivery of bioactive signals to modulate and complement the dynamics of the wound healing process, making these materials functional and clinically viable as wound dressings.