GHK-Cu

Abstract

To address the challenges in wound healing, clinical management increasingly demands targeted, adaptive, responsive, and patient-centered strategies. This is especially true for wounds characterized by delayed healing and a high risk of infection. Advances in regenerative medicine and biomaterial technologies are fostering the development of multifunctional approaches that integrate tissue regeneration, antibacterial/antibiofilm activity, immunomodulation, and real-time monitoring. This paper surveys emerging platforms, including both natural and synthetic scaffolds, hydrogels enriched with platelet-derived growth factors, glycosaminoglycan mimetics, bioactive peptides (such as GHK-Cu and antimicrobial peptides), nanoscaffolds, and stimuli-responsive systems. The paper also explores cutting-edge technologies such as water-powered, electronics-free dressings that deliver localized electrical stimulation; biodegradable bioelectric sutures that produce self-sustained mechano-electrical signals; and sensory bandages that monitor pH, moisture, temperature, and bacterial contamination in real-time while enabling on-demand drug release with pro-regenerative, antibacterial, and other therapeutic functionalities. Further therapeutic approaches include natural matrices, exosomes, gene editing, 3D bioprinting, and AI-assisted design. Particular attention is paid to orthopedic applications and orthopedic implant infection. A brief section addresses the still unresolved challenge of articular cartilage regeneration. Interdisciplinary innovation, integrating insights from molecular biology through engineering, plays a central role in translating novel strategies into tailored, clinically effective wound management solutions.

Abstract

Therapeutic peptides are emerging as promising adjuncts in the management of orthopaedic injuries, grounded in their ability to modulate molecular signaling networks central to cellular medicine. By acting on key pathways such as PI3K/Akt, mTOR, MAPK, TGF-β, and AMPK, peptides exert influence over tissue regeneration, inflammation resolution, and neuromuscular recovery. Wound-healing peptides such as BPC-157, TB-500, and GHK-Cu promote angiogenesis, integrin-mediated extracellular matrix remodeling, and fibroblast activation, whereas growth hormone secretagogues like ipamorelin, CJC-1295, tesamorelin, sermorelin, and AOD-9604 activate IGF-1 signaling and satellite cell repair. Recovery-enhancing agents such as epithalon, delta sleep-inducing peptide, and pinealon target circadian and mitochondrial regulators, and neuroactive peptides like selank, semax, and dihexa enhance brain-derived neurotrophic factor and HGF/c-Met pathways critical to neuroplasticity. Although preclinical studies are promising, there is a current lack of clinical trials. This review integrates current mechanistic insights with orthopaedic relevance, emphasizing safety, efficacy, and future directions for responsible integration into musculoskeletal care.

Abstract

Therapeutic peptides are short-chain amino acids that regulate cellular functions and facilitate biochemical processes. In recent years, there has been significant growth in the global market for therapeutic peptides and thus its popularity among patients. Given the increase in the development of peptides and increased marketing to patients for orthopaedic injuries, it is critical for orthopaedic surgeons to understand the current evidence behind these therapeutic peptides.

Abstract

With the wide application of soft tissue fillers, implant material-induced inflammatory reactions have become a key factor affecting the therapeutic efficacy. This study developed an injectable filler with enhanced anti-inflammatory and antioxidant effects by adsorbing glycyl-L-histidyl-L-lysine copper complex (GHK-Cu) onto hydroxyapatite microspheres (HAPs), marking the first combination of HAPs and GHK-Cu to address inflammation caused by soft tissue fillers. GHK-Cu was successfully loaded onto HAPs by electrostatic adsorption. HAPs were then mixed with carboxymethyl cellulose (CMC), glycerol (GLY), and water to form GHK-Cu@CMHA gel. The study focus on the effective combination of HAPs as a carrier for sustained GHK-Cu delivery and the anti-inflammatory properties of GHK-Cu. GHK-Cu@CMHA exhibits sustained release properties for 7 days, which ensures prolonged therapeutic effects, minimizes peptide waste and reduces injection frequency, with good flowability and injectability. In the model of LPS-induced inflammation model in vivo and in vitro, GHK-Cu@CMHA gel reduced levels of inflammatory factors and Reactive oxygen species (ROS) levels decreased, while superoxide dismutase (SOD) activity was enhanced. In this process, H&E staining and Masson staining revealed significant collagen deposition. These findings further confirm that GHK-Cu@CMHA is a novel injectable soft tissue filler with good anti-inflammatory and antioxidant properties, which holds well potential for inflammation inhibition.

Abstract

In recent years, hyaluronic acid (HA) and the natural tripeptide glycyl-l-histidyl-l-lysine (GHK), especially its copper(II) complex (GHK-Cu), individually have been shown to exert helpful properties for bone protection and regeneration. However, they are not strong enough to handle oxidative stress, hydrolytic attack, or environmental conditions. Being aware that conjugation chemistry has recently emerged as an appealing approach for generating new molecular entities capable of preserving the molecular integrity of their moieties or delaying their degradation, herein we present the synthesis of conjugates of HA with GHK (GHK-HA), at different loadings of the tripeptide. GHK-HA binds copper(II) ions and potentiates the chemical and biological properties of the two components in in vitro assays. The results highlight copper's role in promoting the expression and release of certain trophic, angiogenic, and osteogenic factors, including brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), as well as bone morphogenetic protein-2 (BMP-2). The protective and regenerative activities of the metal ion are related to the translocation of its intracellular chaperones Copper Chaperone for Superoxide Dismutase (CCS) and Antioxidant-1 (Atox1) to the nucleus where they act as transcription factors.

Abstract

Glycyl-l-histidyl-l-lysine (GHK) tripeptides are known for their remarkable therapeutic potential, including wound-healing, anti-inflammatory activity, and cellular regeneration. However, their clinical application has been significantly hindered by poor biological stability and limited efficacy in a physiological medium. In this study, we introduce a sophisticated approach to overcome these limitations by developing supramolecular peptide nanofiber-gold (Au) nanoparticle (NP) hybrids functionalized with GHK tripeptides. By strategically manipulating peptide self-assembly and NP integration, we demonstrated a useful platform that enhances both therapeutic efficacy and material stability. Our methodology involves the precise engineering of 9-fluorenylmethoxycarbonyl-diphenylalanine scaffolds with GHK and KHG tripeptides, enabling robust nanofibril formation through π-π stacking and hydrogen bonding. Critically, we discovered that the specific amino acid sequence significantly influences the surface exposure of lysine, directly impacting the nanohybrid's wound-healing capabilities. The resultant nanohybrids exhibit exceptional characteristics: Au NPs are spatially confined within the peptide nanofibers, achieving a remarkably uniform size distribution of approximately 3 nm. These nanohybrids demonstrate superior near-infrared (NIR) light absorption and photothermal conversion efficiency, enabling effective eradication of cancer cells and organoids killing under NIR irradiation. This dual-functional nanohybrid integrates biocompatible and enzymatically degradable peptide scaffolds to achieve synergistic wound-healing and cancer-killing effects. By mitigating the cytotoxicity and biodegradability issues associated with conventional photothermal agents, our system provides a promising strategy to improve postoperative cancer therapy and promote tissue regeneration. This work highlights the potential of peptide-inorganic nanohybrids in advancing multifunctional therapeutic platforms for cancer treatment and tissue repair.

Abstract

Peptides are promising and attractive anti-wrinkle active ingredients, amongst which glycyl-histidyl-lysine peptide (GHK) is one of the most broadly promoted peptide for topical application. This simple sequence of amino acid residues not only has the capability of tissue regeneration and the enhancement of collagen and glycosaminoglycans synthesis but also is able to increase nerve outgrowth and angiogenesis. Consequently, GHK has several properties, from wound healing to prevention/reduction wrinkles. GHK-Cu and Pal-GHK are metal complex and palmitoylated derivatives of GHK, respectively. Although GHK-Cu and Pal-GHK are widely used in anti-wrinkle products available on the cosmetic market, the published information on their skin permeability, effectiveness, physicochemical properties and so on is insufficient.