The use of peptides, aptamers, and variable domains of heavy chain only antibodies in tissue engineering and regenerative medicine.

Over the years, much research has been focused on the use of small molecules such as peptides or aptamers or more recently on the use of variable antigen-binding domain of heavy chain only antibodies in the field of tissue engineering and regenerative medicine. The use of these molecules originated as an alternative for the larger conventional antibodies, of which most drawbacks are derived from their size and complex structure. In the field of tissue engineering and regenerative medicine, biological functionalities are often conjugated to biomaterials in order to (re-)create an in vivo like situation, especially when bioinert biomaterials are used. Those biomaterials are functionalized with these functionalities for instance for the purpose of cell attachment or cell targeting for targeted drug delivery but also for local enrichment or blocking of ligands such as growth factors or cytokines on the biomaterial surface. In this review, we further refer to peptides, aptamers, and variable antigen-binding domain of heavy chain only antibodies as biological functionalities. Here, we compare these biological functionalities within the field of tissue engineering and regenerative medicine and give an overview of recent work in which these biological functionalities have been explored. We focus on the previously mentioned purposes of the biological functionalities. We will compare structural differences, possible modifications and (chemical) conjugation strategies. In addition, we will provide an overview of biologicals that are, or have been, involved in clinical trials. Finally, we will highlight the challenges of each of these biologicals. STATEMENT OF SIGNIFICANCE: In the field of tissue engineering there is broad application of functionalized biomaterials for cell attachment, targeted drug delivery and local enrichment or blocking of growth factors. This was previously mostly done via conventional antibodies, but their large size and complex structure impose various challenges with respect of retaining biological functionality. Peptides, aptamers and VHHs may provide an alternative solution for the use of conventional antibodies. This review discusses the use of these molecules for biological functionalization of biomaterials. For each of the molecules, their characteristics, conjugation possibilities and current use in research and clinical trials is described. Furthermore, this review sets out the benefits and challenges of using these types of molecules for different fields of application.